Lentivirally-mediated stem cells to treat Duchenne muscular dystrophy

Lead Research Organisation: University College London
Department Name: Institute of Child Health

Abstract

Duchenne muscular dystrophy (DMD) is an X-linked condition in which muscle fibres degenerate due to the lack of the protein dystrophin. Stem cells, called satellite cells, within skeletal muscle do repair and regenerate lost fibres, but as the new fibres remain dystrophin-deficient, they continually break down, eventually leading to loss of muscle fibres and replacement by fat and connective tissue. If we want to use stem cells to treat DMD, these would have to be a type of stem cell that can be delivered via the blood system, as DMD affects all the muscles of the body. We propose to use stem cells derived from the patient themselves, so that they would not promote immunonological rejection. We aim to engineer these stem cells so that they have a heritable copy of the dystrophin gene. But the whole dystrophin gene is too large to fit into any viral vector. We will therefore engineer the dystrophin gene to be small enough to fit into a lentiviral vector, but large enough to contain as much as possible of the gene, to make it as functional as possible. Combining the best stem cell to regenerate skeletal muscle with the optimal dystrophin gene will pave the way for clinical trials to treat DMD.

Technical Summary

Genetic correction of autologous stem cells is a potential therapy for Duchenne muscular dystrophy (DMD). However, key questions need to be resolved before this approach could be realistically used in DMD. These include the determination of the best stem cell and a safe lentivirus containing a dystrophin gene that is small enough to fit into the vector, yet large enough to code for a functional protein. We aim to design a safe lentiviral vector, coding for an effective dystrophin gene (opti-dystrophin). In parallel, we will compare the ability of induced pluripotent stem cells (iPS) and adult stem cells (AC133+ cells), firstly of mouse origin and then of human origin, to efficiently regenerate skeletal muscle and functionally reconstitute the satellite cell (muscle stem cell) pool following intra-arterial injection in an immunodeficient mouse model of DMD. We will then combine the optimised lentivirus with the most favourable stem cell of DMD origin and test this in our in vivo model. Solving these preclinical questions will allow us to plan for future clinical trials for DMD.

Publications

10 25 50

 
Description Association Française contre les myopathies
Amount £18,521 (GBP)
Funding ID 16820 
Organisation French Muscular Dystrophy Association (AFM) 
Sector Charity/Non Profit
Country France
Start 11/2012 
End 10/2013
 
Description BBSRC
Amount £666,193 (GBP)
Funding ID BB/J005436/1 
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 06/2012 
End 05/2015
 
Description Building the Knowledge Base for Therapy Development in Duchenne Muscular Dystrophy
Amount £75,000 (GBP)
Organisation Action Duchenne 
Sector Charity/Non Profit
Country United Kingdom
Start 07/2015 
End 06/2020
 
Description Child Health Research Appeal Trust
Amount £36,292 (GBP)
Funding ID 2011 PhD-03 
Organisation Child Health Research Appeal Trust (CHRAT) 
Sector Charity/Non Profit
Country United Kingdom
Start 10/2011 
End 09/2014
 
Description Research grant
Amount € 23,000 (EUR)
Funding ID 16280 
Organisation French Muscular Dystrophy Association (AFM) 
Sector Charity/Non Profit
Country France
Start 11/2012 
End 10/2013
 
Description Research leadership
Amount £116,126 (GBP)
Funding ID V1300 
Organisation Great Ormond Street Hospital Children's Charity (GOSHCC) 
Sector Charity/Non Profit
Country United Kingdom
Start 04/2013 
End 03/2016
 
Description Restoration of full length dystrophin in induced pluripotent stem cell derived muscle progenitor cells
Amount £225,000 (GBP)
Funding ID 17GRO-PG36-0165 
Organisation Muscular Dystrophy UK 
Sector Charity/Non Profit
Country United Kingdom
Start 12/2017 
End 11/2020
 
Description Validation of Serum Biomarkers for DMD
Amount £21,230 (GBP)
Organisation French Muscular Dystrophy Association (AFM) 
Sector Charity/Non Profit
Country France
Start 01/2015 
End 12/2016
 
Title DMD patients 
Description DMD patients biological material (primary cell cultures) 
Type Of Material Biological samples 
Year Produced 2008 
Provided To Others? Yes  
Impact Publications 
URL https://www.ncbi.nlm.nih.gov/pubmed/24920607
 
Description Stem cells that contribute to skeletal muscle regeneration 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Postgraduate students
Results and Impact Stem cells that contribute to skeletal muscle regeneration - invited talk. MyoGrad, Paris June 2017.
Year(s) Of Engagement Activity 2017
 
Description 18th International Congress of the World Muscle Society; Pacific Grove, California, USA 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact 18th International Congress of the World Muscle Society; Pacific Grove, California, USA
October 2013
Optimised dystrophin mini-constructs for gene delivery to skeletal muscle


Fellowship award for the submitted abstract for poster presentation at the 18th International Congress of the World Muscle Society; Pacific Grove, California, USA - awarded to Mojgan Reza
Year(s) Of Engagement Activity 2013
 
Description 3rd Annual Conference MRC Centre for Neuromuscular Diseases 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Poster Presentation
Geographic Reach National
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact Attended by approximately 300 researchers. Conference held in the Dubowitz Neuromuscular Centre, Institute of Child Health, London. Poster entitled "Optimal Mini-Dystrophin Construct for Gene Delivery to Skeletal Muscle: Project overview and preliminary results".

An opportunity to discuss progress with prominent researchers working in the field.
Year(s) Of Engagement Activity 2011
 
Description 4th Annual Conference MRC Centre for Neuromuscular Diseases 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Poster Presentation
Geographic Reach National
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact Approximately 300 researchers attended this event in Newcastle Upon Tyne. Presentation was entitled "Mini-Dystrophin Constructs for Gene Delivery to Skeletal Muscle; Project overview and preliminary results".

Opportunity to discuss current research with researchers working in the field.
Year(s) Of Engagement Activity 2012
 
Description Action Duchenne Conference 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Paper Presentation
Geographic Reach National
Primary Audience Participants in your research and patient groups
Results and Impact Annual conference for those affected by Duchenne Muscular Dystrophy and attended by approximately 200 people. Presentation was entitled "Stem cells for Duchenne Muscular Dystrophy". Location was the Holiday Inn, Bloomsbury, London. Good engagement from the audience.

Invited again in 2012 given the interest from parents in stem cell related research for Duchenne Muscular Dystrophy.
Year(s) Of Engagement Activity 2011
 
Description Action Duchenne Conference 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Participants in your research and patient groups
Results and Impact Approximately 200 parents attended this conference and asked questions following the presentation

Nothing at this stage but it is likely that an update on this research will be given at the next annual conference
Year(s) Of Engagement Activity 2011
 
Description Institute seminar; Institute of Genetic Medicine, International Centre for Life, Newcastle University 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach Local
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact June 2013: Institute seminar; Institute of Genetic Medicine, International Centre for Life, Newcastle University
Optimised dystrophin mini-constructs for gene delivery to skeletal muscle
Talk by Mojgan Reza

None
Year(s) Of Engagement Activity 2013
 
Description Is there a future for cell therapy? 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Patients, carers and/or patient groups
Results and Impact Is there a future for cell therapy? - invited talk. Action Duchenne conference, November 2017.
Year(s) Of Engagement Activity 2017
 
Description PhD-student research day; Institute of Genetic Medicine, International Centre for Life, Newcastle University 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Type Of Presentation Poster Presentation
Geographic Reach National
Primary Audience Postgraduate students
Results and Impact January 2013: PhD-student research day; Institute of Genetic Medicine, International Centre for Life, Newcastle University
Optimal dystrophin construct for gene delivery to skeletal muscle
Poster presentation by Mojgan Reza

none
Year(s) Of Engagement Activity 2013
 
Description Skeletal muscle stem cells and Duchenne muscular dystrophy 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Skeletal muscle stem cells and Duchenne muscular dystrophy - invited talk. H3 Muscle physiology and metabolism symposium, The Physiological Society, London, November 2017
Year(s) Of Engagement Activity 2017
 
Description Stem Cells and Muscular dystrophies 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Postgraduate students
Results and Impact Stem Cells and Muscular dystrophies - invited talk. Royal Holloway, University of London January 2017.
Year(s) Of Engagement Activity 2017
 
Description The 10th Annual Conference of the British Society for Gene and Cell Therapy, Royal Holloway, University of London 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Poster Presentation
Geographic Reach National
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact Poster presentation: Development of a recombinogenic lentivirus for the transfer of Human Dystrophin cDNA to DMD stem cells
Authors: John Counsell, Veronica Ferrer, Jinhong Meng, Francesco Muntoni, Jennifer E Morgan, and Olivier Danos


none
Year(s) Of Engagement Activity 2013
 
Description The 10th Annual Conference of the British Society for Gene and Cell Therapy, Royal Holloway, University of London 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Poster Presentation
Geographic Reach National
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact 17-19 April 2013. The 10th Annual Conference of the British Society for Gene and Cell Therapy, Royal Holloway, University of London. "Jinhong Meng, Rowan Asfahani, Soyon Chun, Francesco Muntoni and Jennifer E. Morgan. Human skeletal muscle-derived AC133+ cells form functional muscle stem cells after intramuscular transplantation into immunodeficient host mice"

none.
Year(s) Of Engagement Activity 2013
 
Description UK Neuromuscular Translational Research Conference 2013, Oxford 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Poster Presentation
Geographic Reach National
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact 14th - 15th March, 2013. UK Neuromuscular Translational Research Conference 2013, Oxford. "Jinhong Meng, Rowan Asfahani, Soyon Chun, Francesco Muntoni and Jennifer E. Morgan. Human skeletal muscle-derived AC133+ cells form functional muscle stem cells after intramuscular transplantation into immunodeficient host mice"

none
Year(s) Of Engagement Activity 2013