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Molecular Genetic Therapies Group
Background:
Our objectives are to develop a treatment for Duchenne muscular dystrophy and reduce the severity of this disease.
Projects and techniques
Antisense oligomer induced exon skipping to restore dystrophin expression
Oligomer design
Muscle gene mutation analysis
Muscle gene expression studies
Gene down regulation
The Molecular Genetic Therapy Group investigates experimental therapies for neuromuscular diseases, with a focus on Duchenne muscular dystrophy. The main research interests are the manipulation of transcript splicing to modify gene expression for therapeutic outcomes. We use antisense oligomers to alter the exon structure of a target transcript in order to remove or by-pass protein truncating mutations and thereby reduce the impact of a genomic lesion on muscle function.
Projects:
Duchenne muscular dystrophy (DMD) is a progressive muscle wasting disorder with limited treatment options. DMD is caused by protein truncating mutations in the large dystrophin gene, and affects about 1 out of every 3500 boys. Analysis of the dystrophin gene structure in Becker muscular dystrophy (BMD) patients has revealed that some parts of the gene are variably dispensable, with minimal functional consequences. We have shown that it is possible to produce dystrophin gene transcripts in DMD patients that emulate those found in BMD patients, by excluding selected exons in the region of the mutation.Antisense oligomers can be used to block the inclusion of an exon carrying a nonsense mutation, or to remove exons flanking a frame-shifting deletion to restore the dystrophin reading frame and produce a functional protein.
We first demonstrated the removal of a dystrophin exon carrying a mutation 10 years ago. At the end of 2007, one of our compounds entered clinical trials and was injected into the muscle of a DMD boy.
Clinic:
Exon Skipping trials.
Antisense compounds, developed by our group, to address human dystrophin mutations have been licensed to AVI Biopharma for clinical development. Phase 1 of the clinical trial undertaken in the UK using a compound for the treatment of Duchenne muscular Dystrophy (DMD) developed by an international team of investigators that included Professor Steve Wilton has yielded promising results.
The study involved injecting the compound into a muscle in the foot of a DMD affected boy and a quantity of a salt solution into the corresponding muscle on the other foot. Three to four weeks later, each injected muscle was examined for evidence of dystrophin production. Results showed the compound injected foot muscles produced dystrophin in all participants, and that the amount produced correlated with the injected dose. All participants tolerated the compound well, and there were no significant adverse reactions related to its administration.
Biopsies from muscles injected with the higher dose of test drug showed an unequivocal, widespread and robust response in terms of number of dystrophin positive muscle fibers. A systemic (intravenous) delivery and a study to develop exon skipping for other diseases will now be investigated.