Project partners

University College London

Institute of Child Health



UCL Institute of Child Health (ICH) which, together with its clinical partner Great Ormond Street Hospital for Children (GOSH), forms the largest concentration of children’s health research outside North America. ICH pursues an integrated, multidisciplinary approach to enhance understanding, diagnosis, therapy and prevention of childhood disease.  A broad range of paediatric issues is covered, from molecular genetics to population health sciences. All specialties as they relate to children’s health are included so that ICH fulfils the role of a world-leading academic establishment in paediatrics.  In keeping with a commitment to disease prevention, ICH is active in teaching and research aimed at developing interventions to promote health both during childhood and in the later years of life. This multi-disciplinary approach is necessitated by the important principle that the child is not merely a small adult. 

ICH was established in 1945 and, in 2006, joined UCL's newly-formed Faculty of Biomedical Sciences, becoming the largest of its 14 Divisions and Institutes. ICH has maintained a particularly close relationship with GOSH throughout its sixty-three year existence. These close links have enabled ICH to pursue medical research in the context of child health and disease, based upon an integrated approach of careful clinical observation and scientific investigation. This allows an understanding of disease mechanisms and, in turn, leads to precise diagnosis and development of new therapies.

The Dubowitz Neuromuscular Centre (DNC) is part of the ICH. It provides a multidisciplinary service as a leading clinical and research centre specialising in neuromuscular disorders affecting children. The DNC provides clinical assessment, diagnostic services and advice on treatment and rehabilitation. The DNC is also involved in clinical trials, basic research focusing on understanding the cause of neuromuscular diseases in childhood and identifying novel therapeutic intervention.

UCL Institute of Child Health's Mission Statement:

Improve the health and wellbeing of children, and the adults they will become, through world-class research, education and public engagement.


University College London Website
UCL Institute of Child Health website
Dubowitz Neuromuscular Centre Website

Contact: Francesco Muntoni
Email Francesco

Dubowitz Neuromuscular Unit
1st Floor Institute of Child Health
30 Guildford Street
London
WC1N 1EH
United Kingdom
Tel: +44 (0) 20 7905 2111
Fax: +44 (0) 20 7905 2832

 

 

University College London and BIO-NMD

UCL Institute of Child Health will be involved in the collection and distribution of biomaterials for the research (e.g. muscle cells, blood and urine from Duchenne muscular dystrophy patients).  We have access to these samples via the MRC Centre for Neuromuscular Diseases biobank.  We will also be involved in the discovery of both genetic and protein biomarkers that would indicate differences in disease progression and/or response to potential therapeutic agents.  The goal is to have a non-invasive way of monitoring disease severity or treatment benefit, e.g. by measuring levels of a protein in the blood or urine. UCL Institute of Child Health will contribute mainly to WPs 1 - Patients' material organisation, circulation and managing of novel patients' fluids collection; 2 - Genomic biomarkers discovery by genome-wide analyses of DNA and RNA; and 3 - Proteomic biomarkers discovery by studies on patient cells, muscle tissues and body fluids.

 

Francesco Muntoni - Professor of Paediatric Neurology, Director



Francesco Muntoni leads the Dubowitz Neuromuscular Centre.
The goals of his research are to:

  1. elucidate the genetic and the molecular basis of a group of diseases called congenital muscular dystrophies
  2. regulation of splicing in Duchenne muscular dystrophy and spinal muscular atrophy.
  3. characterize muscle stem cells for possible future therapeutic applications

1. Molecular basis of congenital muscular dystrophies
Our group has identified 2 novel loci for forms of congenital muscular dystrophy and 3 novel disease genes. In 2001 we identified mutations in the FKRP gene in a CMD variant called MDC1C; shortly after we discovered that milder mutations in the same gene were also responsible for one of the most common forms of limb girdle muscular dystrophy (LGMD2I). In a few children with severe MDC1C there is evidence of brain involvement.
Mutations in FKRP identified a novel pathway responsible for both muscular degeneration and neuronal migration defects, aspects which are being further characterised in a relevant knock-in animal model, produced in collaboration with Dr Susan Brown (Imperial College).

In 2005 we discovered that mutations in the human LARGE gene cause MDC1D, another form of congenital muscular dystrophy. Recent work indicate that overexepression of this gene can restore normal dystroglycan ligand binding in cells from patients with a dystroglycanopathy. Upregulation of LARGE expression appears to be a plausible therapeutic approach in these disorders and to explore this further we have generated several transgenic lines (in collaboration with Prof Nic Wells, Imperial College) expressing a LARGE transgene. The long term aim is to see if this approach is capable of rescuing the phenotype in dystrophic animals.

We have also established an international collaboration networks allowing the identification of a number of disease loci and genes involved in other forms of neuromuscular disorders (13 different disorders in collaboration with external collaborators).

2. Regulation of splicing
We work on regulating splicing of the SMN2 gene in spinal muscular atrophy; and in antisense oligonucleotide induced exon skipping in Duchenne muscular dystrophy. This latter interest culminated in a Department of Health funded grant to establish a consortium for a phase I/II therapeutic trial of antisense oligonucleotides in Duchenne muscular dystrophy that started in 2005 (MDEX consortium, www.mdex.org.uk, of which Prof Muntoni is the Principal Investigator). In view of the exciting preclinical data generated by this project, we have recently obtained an MRC translational research grant to extend this study into a repeated intravenous antisense administration into young boys with Duchenne.

The work on spinal muscular atrophy is performed in collaboration with Prof Ian Eperon, Leicester University. We have devised a novel approach (tailed oligonucleotides or TOES), to induce exon INCLUSION in the SMN2 gene. We are currently validating lead compounds that could have potential therapeutic applications.

 

Jenny Morgan



Jennifer Morgan’s research programme is focused on the cells that contribute to the regeneration of skeletal muscle and environmental conditions that either promote, or inhibit, their function. The principal muscle stem cell is the satellite cell, found under the basal lamina of skeletal muscle fibres.  Some, but not all, satellite cells are able to regenerate skeletal muscle and reconstitute the satellite cell niche with functional satellite cells.  We are currently attempting to define and purify this “stem” sub-population of satellite cells.  We are investigating donor satellite cell regeneration following their grafting into dystrophic host muscles injured in different ways, with the ultimate aim of identifying environmental factors critical for satellite cell regeneration and self-renewal.  We are also examining the capacity of other stem cells, e.g. mesenchymal stem cells, pericytes and mesoangioblasts, to contribute to skeletal muscle regeneration and self-renewal in our mouse model.

 
 




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