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Nucleic Acid Gene Therapy in Brain and Muscle

A. Peptide conjugated oligonucleotide uptake into muscle stem cells (myoblasts; upper panels) and into mature myotubes (lower panels). B. microRNA array identifying extracellular microRNAs elevated in mdx mouse serum and normalised following peptide-conjugated oligonucleotide therapy
A. Peptide conjugated oligonucleotide uptake into muscle stem cells (myoblasts; upper panels) and into mature myotubes (lower panels). B. microRNA array identifying extracellular microRNAs elevated in mdx mouse serum and normalised following peptide-conjugated oligonucleotide therapy

In recent years RNA has emerged as central to understanding cell regulation and disease susceptibility and also as a target for therapeutic intervention. Both single- and double-stranded non-coding RNAs appear to play an important role in regulating the flow of genetic information. Moreover RNA itself can be the target of therapeutic intervention, typically with the use of short DNA or RNA like nucleic acid agents known as oligonucleotides. We are interested in understanding the role of non-coding RNAs and also the potential of oligonucleotide based gene therapy within the neuromuscular system. A major challenge for such therapies is effective delivery to appropriate tissues and cell populations.

RNA biology and therapeutics

Our current research programme is focussed on the study of fundamental RNA biology and the development RNA-based therapeutic agents and novel technologies for their delivery within the context of the neuromuscular system. The recent discovery of endogenous mRNA gene silencing mechanisms known as RNA interference provides a powerful experimental and clinical tool for targeted gene suppression. In contrast, single stranded antisense oligonucleotides are capable modulating the splicing of pre-mRNA splicing to correct the effects of genetic mutations. Our major therapeutic focus is the neuromuscular diseases Duchenne muscular dystrophy (DMD) and spinal muscular atrophy (SMA) and the neurodegenerative disease Parkinson’s disease (PD). Current projects include:

  • Extracellular RNAs and microRNAs in neuromuscular disease
  • Improved delivery of antisense oligonucleotides to muscle and heart utilising novel peptide-conjugated chemistries
  • Studying antisense-mediated exon-skipping of dystrophin in animal models of DMD, focussing on exon skipping in muscle and heart, including functional studies
  • Splice modulation therapy for spinal muscular atrophy
  • Extracellular vesicles for macromolecular drug delivery
  • Non-coding RNAs as biomarkers in neurodegenerative diseases
  • microRNA regulation in stem cell models of Parkinson’s disease

Our team

Related research themes