Keywords: Muscular dystrophy; dystrophin; gene therapy; antisense therapy; RNAi therapy exon skipping; atherosclerosis; neurodegenerative disease; OPMD; DMD; repeat-expansion disease; HIV/ AIDS; vaccines; adenoviral vector; retroviral vector; adeno-associated virus vector; non-viral vectors; apolipoprotein E; apolipoprotein AI; LCAT; PABPN1; dystroglycan; skeletal muscle; utrophin

We are involved in studying the molecular biology and molecular pathology of the nervous, cardiovascular, and skeleto-muscular systems.  The programme involves development of gene therapeutics (lentiviral, adenoviral, adeno-associated virus, non-viral lipoplex vectors, oligonucleotide-based pharmaceuticals), use of transgenic animals and the understanding of signalling pathways in relation to the pathophysiology and treatment of the muscular dystrophies, atherosclerosis and hyperlipidaemia, and neurodegenerative disease.  The work is supported by the European Union, Medical Research Council, Wellcome Trust, Muscular Dystrophy Campaign, British Heart Foundation, Wyeth Discovery, Gates Foundation, Glaxo-SmithKline, Association Francais contre les Myopathies, Muscular Dystrophy Association.

 

1. Development of dystrophin minigenes and viral vectors for treatment of Duchenne muscular dystrophy: preclinical studies in the mdx mouse. 

2. Gene augmentation therapy for atherosclerosis and hyperlipidaemia: muscle-based expression of serum lipoprotein particle components: apolipoprotein E, apolipoprotein A1, lecithin cholesterol acyltransferase (LCAT) and paraoxonase. 

3. Clinical trials and product development for modulation of pre mRNA splicing by antisense oligonucleotides to allow 'skipping' of DMD and other frame-shifting disease mutations. 

4. Genome surgery / correction via targeted DSBs and homologous recombination in the mdx mouse, DMD muscle cells, and lipoprotein genes in the liver. 

5. Utrophin substitution gene therapy vectors to treat muscular dystrophy. 

6. Development of SMAR-based mini-chromosome gene transfer vectors.

7. Muscle gene transfer via simple injection or electrotransfer of naked plasmid DNA, and using lipoplex and polymer carriers.

8. Development of genetic vaccines for HIV/ AIDS

 

Isman O, Roberts M, Morgan J, Graham IR, Goldring K, Watt DJ, Lu Q, Dunckley MG, Porter AC, Partridge TA, Dickson G. Adenovirus-based targeting in myoblasts is hampered by non-homologous vector integration. Hum Gene Ther. 2008 Aug 5. [Epub ahead of print]

Evans V, Foster H, Graham IR, Foster K, Athanasopoulos T, Simons JP, Dickson G, Owen JS. Human apolipoprotein E expression from mouse skeletal muscle by electrotransfer of nonviral DNA (plasmid) and pseudotyped recombinant adeno-associated virus (AAV2/7). Hum Gene Ther. 2008 Jun;19(6):569-78.

Ghahramani Seno MM, Graham IR, Athanasopoulos T, Trollet C, Pohlschmidt M, Crompton MR, Dickson G. RNAi-mediated knockdown of dystrophin expression in adult mice does not lead to overt muscular dystrophy pathology. Hum Mol Genet. 2008 Sep 1;17(17):2622-32.

Papagatsias T, Rozis G, Athanasopoulos T, Gotch F, Dickson G, Patterson S. Activity of different vaccine-associated promoter elements in human dendritic cells. Immunol Lett. 2008 Jan 29;115(2):117-25.

Arechavala-Gomeza V, Graham IR, Popplewell LJ, Adams AM, Aartsma-Rus A, Kinali M, Morgan JE, van Deutekom JC, Wilton SD, Dickson G, Muntoni F. Comparative analysis of antisense oligonucleotide sequences for targeted skipping of exon 51 during dystrophin pre-mRNA splicing in human muscle. Hum Gene Ther. 2007 Sep;18(9):798-810.

McColl BW, McGregor AL, Wong A, Harris JD, Amalfitano A, Magnoni S, Baker AH,  Dickson G, Horsburgh K. APOE epsilon3 gene transfer attenuates brain damage after experimental stroke. J Cereb Blood Flow Metab. 2007 Mar;27(3):477-87.

Foster K, Foster H, Dickson JG. Gene therapy progress and prospects: Duchenne muscular dystrophy. Gene Ther. 2006 Dec;13(24):1677-85.

Ito K, Kimura S, Ozasa S, Matsukura M, Ikezawa M, Yoshioka K, Ueno H, Suzuki M, Araki K, Yamamura K, Miwa T, Dickson G, Thomas GD, Miike T. Smooth muscle-specific dystrophin expression improves aberrant vasoregulation in mdx mice. Hum Mol Genet. 2006 Jul 15;15(14):2266-75.

Rozis G, de Silva S, Benlahrech A, Papagatsias T, Harris J, Gotch F, Dickson G, Patterson S. Langerhans cells are more efficiently transduced than dermal dendritic cells by adenovirus vectors expressing either group C or group B fibre protein: implications for mucosal vaccines. Eur J Immunol. 2005 Sep;35(9):2617-26.

Tagalakis AD, Dickson JG, Owen JS, Simons JP. Correction of the neuropathogenic human apolipoprotein E4 (APOE4) gene to APOE3 in vitro using synthetic RNA/DNA oligonucleotides (chimeraplasts). J Mol Neurosci. 2005;25(1):95-103.

Tagalakis AD, Diakonov IA, Graham IR, Heald KA, Harris JD, Mulcahy JV, Dickson G, Owen JS. Apolipoprotein E delivery by peritoneal implantation of encapsulated recombinant cells improves the hyperlipidaemic profile in apoE-deficient mice. Biochim Biophys Acta. 2005 Jan 5;1686 3:190-9.

Romero NB, Braun S, Benveniste O, Leturcq F, Hogrel JY, Morris GE, Barois A, Eymard B, Payan C, Ortega V, Boch AL, Lejean L, Thioudellet C, Mourot B, Escot C, Choquel A, Recan D, Kaplan JC, Dickson G, Klatzmann D, Molinier-Frenckel V, Guillet JG, Squiban P, Herson S, Fardeau M. Phase I study of dystrophin plasmid-based gene therapy in Duchenne/Becker muscular dystrophy. Hum Gene Ther. 2004 Nov;15(11):1065-76.

Athanasopoulos T, Graham IR, Foster H, Dickson G. Recombinant adeno-associated viral (rAAV) vectors as therapeutic tools for Duchenne muscular dystrophy (DMD). Gene Ther. 2004 Oct;11 Suppl 1:S109-21.

Graham IR, Hill VJ, Manoharan M, Inamati GB, Dickson G. Towards a therapeutic inhibition of dystrophin exon 23 splicing in mdx mouse muscle induced by antisense oligoribonucleotides (splicomers): target sequence optimisation using oligonucleotide arrays. J Gene Med. 2004 Oct;6(10):1149-58.

Ferrer A, Foster H, Wells KE, Dickson G, Wells DJ. Long-term expression of full-length human dystrophin in transgenic mdx mice expressing internally deleted human dystrophins. Gene Ther. 2004 Jun;11(11):884-93.

Manzano A, Mohri Z, Sperber G, Ogris M, Graham I, Dickson G, Owen JS. Failure to generate atheroprotective apolipoprotein AI phenotypes using synthetic RNA/DNA oligonucleotides (chimeraplasts). J Gene Med. 2003 Sep;5(9):795-802.

Harris JD, Beattie SG, Dickson JG. Novel tools for production and purification of recombinant adeno-associated viral vectors. Methods Mol Med. 2003;76:255-67.

Roberts M, Dickson G. The future of Duchenne muscular dystrophy gene therapy: shrinking the dystrophin gene. Curr Opin Mol Ther. 2002 Aug;4(4):343-8.

Dickson G, Hill V, Graham IR. Screening for antisense modulation of dystrophin pre-mRNA splicing. Neuromuscul Disord. 2002 Oct;12 Suppl 1:S67-70.

Dickson G, Roberts ML, Wells DJ, Fabb SA. Recombinant micro-genes and dystrophin viral vectors. Neuromuscul Disord. 2002 Oct;12 Suppl 1:S40-4.

Roberts ML, Wells DJ, Graham IR, Fabb SA, Hill VJ, Duisit G, Yuasa K, Takeda S, Cosset FL, Dickson G. Stable micro-dystrophin gene transfer using an integrating adeno-retroviral hybrid vector ameliorates the dystrophic pathology in mdx mouse muscle. Hum Mol Genet. 2002 Jul 15;11(15):1719-30.

Sakamoto M, Yuasa K, Yoshimura M, Yokota T, Ikemoto T, Suzuki M, Dickson G, Miyagoe-Suzuki Y, Takeda S. Micro-dystrophin cDNA ameliorates dystrophic phenotypes when introduced into mdx mice as a transgene. Biochem Biophys Res Commun. 2002 May 17;293(4):1265-72.

Graham IR, Dickson G. Gene repair and mutagenesis mediated by chimeric RNA-DNA oligonucleotides: chimeraplasty for gene therapy and conversion of single nucleotide polymorphisms (SNPs). Biochim Biophys Acta. 2002 May 21;1587(1):1-6.

Fabb SA, Wells DJ, Serpente P, Dickson G. Adeno-associated virus vector gene transfer and sarcolemmal expression of a 144kDa micro-dystrophin effectively restores the dystrophin-associated protein complex and inhibits myofibre degeneration in nude/mdx mice. Hum Mol Genet. 2002 Apr 1;11(7):733-41.

Harris JD, Schepelmann S, Athanasopoulos T, Graham IR, Stannard AK, Mohri Z, Hill V, Hassall DG, Owen JS, Dickson G. Inhibition of atherosclerosis in apolipoprotein-E-deficient mice following muscle transduction with adeno-associated virus vectors encoding human apolipoprotein-E. Gene Ther. 2002 Jan;9(1):21-9.

Harris JD, Graham IR, Schepelmann S, Stannard AK, Roberts ML, Hodges BL, Hill V, Amalfitano A, Hassall DG, Owen JS, Dickson G. Acute regression of advanced and retardation of early aortic atheroma in immunocompetent apolipoprotein-E (apoE) deficient mice by administration of a second generation [E1(-), E3(-), polymerase(-)] adenovirus vector expressing human apoE. Hum Mol Genet. 2002 Jan 1;11(1):43-58.

Roberts ML, Athanasopoulos T, Pohlschmidt M, Duisit G, Cosset FL, Dickson G. Post-mitotic, differentiated myotubes efficiently produce retroviral vector from hybrid adeno-retrovirus templates. Gene Ther. 2001 Oct;8(20):1580-6.

Stannard AK, Riddell DR, Sacre SM, Tagalakis AD, Langer C, von Eckardstein A, Cullen P, Athanasopoulos T, Dickson G, Owen JS. Cell-derived apolipoprotein E (ApoE) particles inhibit vascular cell adhesion molecule-1 (VCAM-1) expression in human endothelial cells. J Biol Chem. 2001 Dec 7;276(49):46011-6.

Graham IR, Beattie SG, Hill VJ, Dickson G. Oligonucleotide-based gene correction strategies: applications to neuromuscular and cardiovascular diseases. Croat Med J. 2001 Aug;42(4):467-72.

Graham IR, Manzano A, Tagalakis AD, Mohri Z, Sperber G, Hill V, Beattie S, Schepelmann S, Dickson G, Owen JS. Gene repair validation. Nat Biotechnol. 2001 Jun;19(6):507-8.

Tagalakis AD, Graham IR, Riddell DR, Dickson JG, Owen JS. Gene correction of the apolipoprotein (Apo) E2 phenotype to wild-type ApoE3 by in situ chimeraplasty. J Biol Chem. 2001 Apr 20;276(16):13226-30..

Athanasopoulos T, Owen JS, Hassall D, Dunckley MG, Drew J, Goodman J, Tagalakis AD, Riddell DR, Dickson G. Intramuscular injection of a plasmid vector expressing human apolipoprotein E limits progression of xanthoma and aortic atheroma in apoE-deficient mice. Hum Mol Genet. 2000 Oct 12;9(17):2545-51.

Athanasopoulos T, Fabb S, Dickson G. Gene therapy vectors based on adeno-associated virus: characteristics and applications to acquired and inherited diseases (review). Int J Mol Med. 2000 Oct;6(4):363-75.

Fabb SA, Dickson JG. Technology evaluation: AAV factor IX gene therapy, Avigen Inc. Curr Opin Mol Ther. 2000 Oct;2(5):601-6.