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Development of gene therapies for muscular dystrophies

School of Biological Sciences

About the Project

The activities in the Popplewell lab focus on the development of pre-clinical gene therapies for neuromuscular diseases, in particular muscular dystrophies based on gene replacement, endonuclease-mediated gene editing, antisense oligonucleotide (AO)-induced exon skipping and gene sliencing . This involves the engineering and testing of viral (AAV, lentivirus) and non-viral (plasmid, oligonucleotide) gene therapy vectors in pre-clinical models in the areas of Duchenne muscular dystrophy (DMD), fascioscapulohumeral dystrophy (FSHD) and oculopharyngeal muscular (OPMD). Research will involve vector, AO and endonuclease design, their engineering and production, and evaluation of therapeutic efficacy in cell culture and transgenic models of the disorders and will be in one of the following areas: (i) Development of AAV micro-dystrophin gene vectors for DMD gene therapy; (ii) Inhibition of myostatin (GDF8) for treatment of muscle wasting in dystrophic disease; (iii) Development of antisense therapeutics to modulate RNA splicing; (iv) Targeting of specific genes to reverse the muscle fibrosis associated with the muscular dystrophies.

Gene replacement, gene editing, antisense oligonucleotides, muscular dystrophy.


Lu-Nguyen NB, Jarmin SA, Saleh AF, Popplewell L, Gait MJ, Dickson G. (2015). Combination Antisense Treatment for Destructive Exon Skipping of Myostatin and Open Reading Frame Rescue of Dystrophin in Neonatal mdx Mice. Mol Ther. 23(8):1341-8.
Jarmin S, Kymalainen H, Popplewell L, Dickson G (2014). New developments in the use of gene therapy to treat Duchenne muscular dystrophy. Expert Opin Biol Ther. 2014 Feb;14(2):209-30.
Koo T, Popplewell LJ, Athanasopoulos T, Dickson G. (2014). Triple trans-splicing AAV vectors capable of transferring the coding sequence for full-length dystrophin protein into dystrophic mice. Hum Gene Ther. 25(2):98-108
Popplewell L, Koo KY, Leclerc X, Duclert A et al. (2013). Gene Correction of a Duchenne Muscular Dystrophy Mutation by Meganuclease-Enhanced Exon Knock-in. Human Gene Ther 24(7):692-701.
Popplewell LJ, Malerba A, Dickson G. (2012) Optimizing antisense oligonucleotides using phosphorodiamidate morpholino oligomers. Methods Mol Biol; 867:143-67.
Popplewell LJ, Graham IR, Malerba A, Dickson G (2011). Bioinformatic and functional optimization of antisense phosphorothioate morpholino oligomers (PMOs) for therapeutic modulation of RNA splicing in muscle. Methods Mol Ther 709: 153-78.
Koo T, Malerba A, Athanasopoulos T, Trollet C, Boldrin L, Ferry A, Popplewell L, Foster H, Foster K, Dickson G. (2011). Delivery of AAV2/9-Microdystrophin Genes Incorporating Helix 1 of the Coiled-Coil Motif in the C-Terminal Domain of Dystrophin Improves Muscle Pathology and Restores the Level of α1-Syntrophin and α-Dystrobrevin in Skeletal Muscles of mdx Mice.Hum Gene Ther. 22(11):1379-88.
Popplewell LJ, Adkin C, Arechavala-Gomeza V, et al. (2010). Comparative analysis of antisense oligonucleotide sequences targeting exon 53 of the human DMD gene: implications for future clinical trials. Neuromus Disord 20: 102-10.
Popplewell LJ, Trollet C, Dickson G. Graham IR (2009) Design of phosphorodiamaidate morpholino oligomers (PMOs) for the induction of exon skipping of the human DMD gene. Mol Ther 17: 554-61.
Kinali M, Arechavala-Gomeza V, Feng L, Cirak S, Hunt D, Adkin C, Guglieri M, Ashton E, Abbs S, Nihoyannapoulos P, Garralda M, Rutherford M, McCulley C, Popplewell L, et al. (2009) Local Restoration of Dystrophin Expression in Duchenne Muscular Dystrophy: A Single Blind, Placebo-controlled Dose Escalation Study Using Morpholino Oligomer AVI-4658. Lancet Neurology 8: 918-928.

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