UCL Great Ormond Street Institute of Child Health


Great Ormond Street Institute of Child Health


Research projects

Advanced antisense oligonucleotide technology for exon skipping in Duchenne muscular dystrophy

Duchenne muscular dystrophy (DMD) is the most common children's muscular dystrophy. This fatal disorder is due to genetic mutations that cause the lack of a protein (dystrophin) in the patients' muscles. There is currently no cure, but we recently were able to restore small amounts of dystrophin in patients in two clinical trials using a novel type of drug called antisense oligonucleotide (AO). The particular AO used in these trials (Eteplirsen) targets some specific mutations and is only applicable to a percentage of DMD children, as they show a range of different mutations.

While Eteplirsen is now following more advanced clinical trials that would, hopefully, deliver it to the clinic, there are several aspects that we aim to improve from this "first generation AO", not only to target mutations affecting other patients, but also improving many aspects of this AOs, mainly poor distribution to the heart and the need for repeated or high doses. In this project, the MDEX Consortium, a group of preclinical scientists and clinicians based in the UK, in partnership with companies developing RNA therapeutics, plans to focus on the development and optimisation of a safe new generation AOs.

We have gathered the expertise of 6 universities to collaborate in 1) the selection of an new generation AO chemistry to improve the delivery of the drug into skeletal and cardiac muscle, 2) the identification of the best sequences targeting new DMD deletions (those repaired by targeting exon 53) and 3) the optimisation of all the methods used to measure the effectiveness of treatment in patients, all in preparation for new clinical trials..


Funding: Health innovation challenge fund (funding partnership between the Wellcome Trust and the Department of Health).

Developing antisense oligonucleotides therapy for spinal muscular atrophy and other neuromuscular disorders

Our major project is to develop antisense oligonucleotides therapy for spinal muscular atrophy (SMA). The strategy is to augment the splicing of exon 7 in SMN2 gene and consequently to restore functional SMN protein by using the advanced antisense oligonucleotide (AON) technology. Our group has previously developed AONs to induce exon 7 inclusion in SMN2 gene, including both bifunctional and conventional AONs (Owen &Zhou et al. 2011, Nucleic Acids Research; Zhou et al. 2013 Human Gene Therapy). Several very efficient compounds have been developed which exhibited remarkable efficacy in preclinical studies including the successful rescue of severe type I SMA mice. The studies we are currently carrying on include 1) continue the work on developing novel antisense sequences annealing to different intronic or exonic regions of SMN2 gene; 2) studies on dose, routes of delivery, biodistribution and half-life of the oligos and to identify the most optimal administration strategy in mice which will help the design of future clinical trial in patients; 3) developing biomarkers which can be used to indicate disease progression and assess the outcome of AON therapy for in vivo studies and future clinical trials. The ultimate aim of this project is to develop the most efficient AON for SMA which can be moved towards clinical trials in children with SMA.

In addition, a parallel and pilot project on expanding the application of AON therapy for other neuromuscular disorders, for example, congenital myopathy and congenital muscular dystrophy caused by dominant mutations in different genes, has recently initiated. With the rapid development of genetic diagnosis on rare diseases and the improved understanding of molecular bases of these conditions, the strategy of gene intervention using AONs can be extended to more disease areas.

Haiyan Zhou

Funding: UCL Therapeutic Innovation Fund and UCL Biomedical Research Centre.

Finding new genes responsible for congenital myopathies

The aim of this project is to identify new genes responsible for congenital muscular dystrophies and congenital myopathies using diverse in vivo and in vitro approaches.

The congenital muscular dystrophies (CMD) and congenital myopathies (CMYO) are a heterogeneous group of autosomal recessively or dominantly inherited diseases presenting at birth or within the first few months of life, with hypotonia, muscle weakness and contractures. CMDs and CMYO are characterised by marked clinical and genetic heterogeneity. We are aware of the involvement of at least 14 different genes in CMD and 15 different genes in CMYO. Nevertheless, the genetic basis of 50% of CMD and CMYO families is currently unknown, suggesting that several additional genes are involved in their pathogenesis.

We are currently involved in a research project (UK10K project) aimed at the identification of novel genes using the next generation sequencing techniques. This study involves the characterisation of the full exome of approximately 100 individuals affected by CMD and CMYO that are still lacking a molecular diagnosis for their muscle disease.

The data generated from exome sequencing is analysed using a number of bioinformatic tools in an attempt at filtering down the 200,000 variants to the single causative gene. Plausible gene candidates are tested for ability to contribute to skeletal muscle development by assay of patient samples and development of a zebrafish knock down model. Morpholino antisense technology will be used to knock down the corresponding gene in zebrafish embryos after which muscle development will be closely observed during 5 days of growth.

Collaborators: Prof. Phil Beales and  UK10K consortium, Wellcome Trust Sanger Institute,

Funding: Muscular Dystrophy Campaign


Restoration of full length dystrophin in induced pluripotent stem cell derived muscle progenitor cells

MDUK-funded 1 Dec 2017 – 30 Nov 2020.
Jennifer Morgan and Jinhong Meng

Genetically modified patient-derived stem cells are a promising therapeutic option for muscular dystrophies such as Duchenne muscular dystrophy (DMD).  

For DMD, it would be best to restore expression of the entire dystrophin gene, as mini-dystrophins lack vital functional elements.  Most viral vectors lack the capacity to incorporate the entire dystrophin coding sequence, which presents a major bottleneck in developing effective treatments. But we have recently shown for the first time that the full-length dystrophin coding sequence can be inserted into a lentiviral vector and this vector can restore full-length dystrophin (FL-dys) expression in myotubes derived from human skeletal muscle stem cells.

Human skeletal muscle-derived stem cells, particularly those derived from DMD patients, are not ideal for either experimental or therapeutic purposes, as they undergo limited proliferation in vitro and expansion limits their regenerative capacity.   In contrast, induced pluripotent stem cells (iPSCs) can be expanded extensively in vitro, facilitating their genetic manipulation, selection and expansion. We will genetically-correct DMD patient-derived iPSCs with lentivirus containing FL-dys, and differentiate them into myogenic precursor cells. We will investigate the capacity of these precursor cells to contribute to muscle regeneration, restore functional dystrophin and functionally reconstitute the satellite cell pool after their intramuscular injection in immunodeficient dystrophin-deficient mice.

Outcomes from this project will be determining the effectiveness of the lentivirus FL-dys, that would be applicable to treatment of all DMD patients, regardless of their dystrophin mutation.  In addition, we will have ascertained whether iPSC-derived myogenic precursor cells are suitable for future clinical application.   


Assessing regenerative potential of myogenic progenitors derived from CRISPR-corrected human iPSCs for treating muscular dystrophy

Barts Charity and Action Duchenne. 2018- 2021.
Jennifer Morgan, Dr Adam Denny, and Dr Yung-Yao Lin, QMUL.

Muscular dystrophies are debilitating genetic diseases characterised by progressive weakness and wasting of skeletal muscle, which is responsible for voluntary movements and breathing. Gene mutations lead to loss of muscle fibres and their replacement with fat and connective tissue. Current standards of care can delay loss of ambulation, cardiac and respiratory problems, but patients develop progressive weakness leading to immobility.
We aim to advance gene-corrected cell therapy for muscular dystrophies. We will tackle several hurdles using our established isogenic pair of Duchenne muscular dystrophy (DMD) patient- specific and gene-corrected pluripotent stem cells, which are capable of generating an unlimited supply of skeletal muscle stem cells. We will assess whether gene-corrected muscle stem cells contribute robustly to regenerated muscle fibres, replenish the muscle stem cell pool and do not form tumours after engraftment in a DMD mouse model. In parallel, we will elucidate molecular mechanisms that enhance skeletal muscle regeneration in the cellular model of DMD.
Advantages of these gene-corrected autologous muscle stem cells include: 1) extensive expansion in culture; 2) no immunological rejection by the patient; and 3) the transplanted cells should give rise to functional muscle stem cells in the patient for life-long efficacy.


Developing next generation gene therapies for rare diseases

The aim of this project is to optimize viral vector technologies for enhanced gene transfer and gene expression in cells. Through various collaborations with industry and academia, we are investigating transcriptional elements that can help balance therapeutic efficacy with genomic safety in treated cells.

Specifically, we are engineering the backbone of HIV-1-based lentiviral vectors and adeno-associated virus vectors, and combining these novel cassettes with synthetic promoters, to identify constructs that can achieve safe and durable transgene expression in vitro and in vivo. Additionally, we are developing genomic platforms to interrogate the genomic safety of these novel gene therapy vectors, with an emphasis on how they interact with endogenous chromatin.

Collaborators: Prof Simon Waddington, Prof Nick Greene, Prof Paul Gissen

Funders: Wellcome Trust


Developing antisense oligonucleotide therapy for collagen VI-related congenital muscular dystrophy

Collagen VI-related congenital muscular dystrophies (COL6-CMD) are a group of muscular dystrophies caused by recessive and dominant mutations in the three Collagen VI genes (COL6A1, COL6A2 and COL6A3).  COL6-CMDs have a wide clinical spectrum ranging from the severe early-onset Ullrich muscular dystrophy (UCMD) to the milder Bethlem myopathy (BM). There is no cure available for COL6-CMD at present.   
Antisense oligonucleotide (AON) can interfere with gene splicing or induce gene silencing. They are under active development for a number of neuromuscular conditions with a substantial contribution of our group on Duchenne muscular dystrophy and spinal muscular atrophy. We have recently explored the therapeutic application of AON allele-specific silencing approach in selected dominant UCMD mutations and achieved very encouraging results (Marrosu et al. 2017 Molecular Therapy Nucleic Acids). Based on this promising proof-of-principle study, we are now expanding the AON therapy to target more dominant collagen VI mutations, including those representing the most frequent genetic defects in COL6-CMD. We focus on new antisense sequence identification, enhanced delivery of antisense compounds in muscle interstitial fibroblasts and novel chemical modifications in collaboration with world-leading academic and industrial groups in the relevant fields.
Sponsor: Muscular Dystrophy UK
Duration: 01/01/2018 – 31/12/2020
PIs: Professor Francesco Muntoni and Dr Haiyan Zhou
Supported researcher: Dr Sara Aguti

Development of microRNAs as biomarkers and therapeutic targets in children with spinal muscular atrophy

Spinal muscular atrophy (SMA) is one of the most common genetic conditions and a leading genetic cause of infant mortality. It is characterized by muscle atrophy and weakness resulting from motor neuron degeneration in the spinal cord. The disease is caused by the deficiency of SMN protein secondary to loss-of-function mutations in the Survival of Motor Neuron 1 (SMN1) gene.
Experimental therapies, including antisense oligonucleotide (AON) therapy, AAV-mediated SMN1 gene therapy and small molecule therapy, have achieved promising results in preclinical studies and clinical trials and rapid clinical development. SpinrazaTM (Nusinersen, Biogen) is the first FDA approved antisense oligonucleotide drug to treat SMA. Our clinical SMA team at the Great Ormond Street Hospital (GOSH) has since started treating a large cohort of type I SMA patients in the UK. Biological samples, such as blood and cerebral spinal fluid (CSF), have been collected during the regular repeated treatment.

Our objective is to develop molecular biomarkers for SMA patients to indicate disease progression and more importantly in the field of translational medicine, the response to therapeutic intervention. We are using the state-of-the-art technologies, such as next generation sequencing and mass spectrometry, for the identification of molecular biomarkers including microRNAs (Catapano et al. 2016 Molecular Therapy Nucleic Acids), proteomics and transcriptomics. We anticipate the successful identification of lead molecules with great potential for clinical application as biomarkers to predict patients’ response to Spinraza and potentially any other SMN augmenting experimental treatment (gene therapy and small molecular therapy), and to facilitate the experimental therapy development in SMA.

Sponsor: NIHR Great Ormond Street Hospital Biomedical Research Centre
Duration: 01/07/2018 – 31/12/2019
PIs: Professor Francesco Muntoni, Dr Mariacristina Scoto and Dr Haiyan Zhou
Supported researchers: Drs Bruno Doreste and Mathilde Sanson


Statistical modelling of disease progression in Spinal Muscular Atrophy and Duchenne Muscular Dystrophy

This project will collect and analyse big data sources on the natural history disease progression of children with Spinal Muscular Atrophy (SMA) and Duchenne Muscular Dystrophy DMD). Currently some treatments are available for both these conditions in the UK, and many clinical trials are ongoing, with further therapeutic options on the way. A better understanding of the natural history of SMA and DMD patients, especially the evolution of more novel considerations such as body composition, nutritional and metabolic status as well as motor function, can help in improving the clinical management of patients and their comorbidities, assessing efficacy of treatments, profiling disease progression, and designing clinical trials. The aim of the project is to collate and use advanced statistical modelling to analyse both retrospective and prospective data on body composition, growth patterns, nutritional status, motor and respiratory function in DMD and SMA untreated and treated patients, in order to provide natural history data and assess the effects of different therapeutics options.

Dr Giovanni Baranello (PI); UCL PhD studentship


Longitudinal study of growth patterns, body composition, energy expenditure and dietary intake in children with Spinal Muscular Atrophy and Duchenne Muscular Dystrophy 

This project addresses an important, still undefined matter related to the nutritional requirements and growth patterns of children with Spinal Muscular Atrophy (SMA) and Duchenne Muscular Dystrophy (DMD). An appropriate nutritional intervention, especially in children, requires a thorough disease-specific knowledge of the energy needs in relation to age, weight, body composition and co-morbidities. However, a consensus on the nutritional management to prevent weight again and relative co-morbidities in SMA and DMD is not available, and longitudinal data on growth pattern, body composition, energy expenditure and dietary habits are highly needed.  The aim of the project is to collect prospective data on nutritional status, body composition, energy requirements and growth pattern in children with SMA and DMD, and to correlate these data with motor function and comorbidities. Appropriate nutritional management is essential in neuromuscular disorders, to reduce fatigability, prevent excessive weight gain or undernutrition, improve function and reduce the negative effects related to different comorbidities, including gastrointestinal symptoms and delayed recovery from acute respiratory events or hospitalizations due to inadequate caloric supply. Furthermore, the use of drugs as steroids in DMD can further complicate the global picture with related side effects such as overweight and metabolic abnormalities. Finally, the ever expanding landscape of emerging treatments for SMA and DMD further highlights the need to have sufficient natural history data to assess the efficacy of therapies on body function and structure as well as quality of life.  

Dr Giovanni Baranello (PI); Sarah Raquq PhD student 

The BIND project

he BIND project is the first project of this scale to improve characterisation of brain involvement in Duchenne and Becker Muscular Dystrophy (DMD and BMD respectively), a previously overlooked field. This EU-funded project connecting 19 partners aims to address a crucial aspect of DMD and BMD that was already recognised in 1861, when Duchenne de Boulogne first described the neuromuscular condition. In the last few decades however, most of the efforts have focused on improving outcomes related to muscle weakness, whilst brain involvement has received less attention.   

The BIND project’s ambition is to elucidate the role of dystrophin in the brain. This protein is deficient in DMD and only partly functional in BMD. The project aims to develop new outcome measures that could inform the field for future clinical trials and will promote more rigorous assessment and intervention of brain comorbidities. The ultimate goal of this project is to improve understanding and measurement of dystrophin in the brain, thus working towards better treatments, care and outcomes for all those living with DMD and BMD. 

Most clinical experts are aware of the occurrence of brain comorbidities in a proportion of individuals affected by DMD and BMD. These X-linked recessive disorders are the result of absent or partly functioning dystrophin protein in muscle. Improved standards of care and novel therapies have greatly improved the quality and quantity of life for DMD and BMD patients over the past decade.   

Project goals:

Localising the isoforms that the DMD locus produces in the brain  and their function;  

Improve understanding of postnatal brain  restoration of  the different dystrophin isoforms using preclinical models;  

Defining the spectrum of brain comorbidities in DMD and BMD individuals, and how to best assess them;  

Creating optimal and uniform outcome measures to assess brain comorbidities in DMD and BMD.  

As well as being of great importance for the Duchenne and Becker community, this project might also benefit the broader neuromuscular and neurodevelopmental field. Brain comorbidity neurobiology is poorly understood, and standards of care not widely disseminated and implemented. This four-year project describing the contribution of a specific protein (dystrophin) to brain function could be of crucial value for the broader neurobiology field, including autistic spectrum disorders. 

Click here to access the official press release (link).