Gene therapy development for various muscular dystrophies

Our research focuses on the pre-clinical development of gene therapies for neuromuscular diseases, in particular the muscular dystrophies based on gene addition, endonuclease-mediated gene editing, antisense oligonucleotide (AO)-induced exon skipping and gene silencing. 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), facioscapulohumeral muscular dystrophy (FSHD) and oculopharyngeal muscular dystrophy (OPMD).

Research involves vector, AO and endonuclease design, their engineering and production, and evaluation of therapeutic efficacy in cell culture and transgenic disease models. The work is focused in the following areas: (i) Development of antisense therapeutics to modulate RNA splicing to restore dystrophin expression for DMD; (ii) Exploration of means to enhance delivery of AOs; (ii) Optimisation and in testing of AOs to knockdown toxic DUX4 expression in models of FSHD; (iii) Targeting of specific genes with AOs and catalytically-inactive CRISPR/Cas9 tethered to transcriptional activators and inhibitors to modulate muscle fibrosis and myogenesis; (iv) Development of endonucleases for editing of the dystrophin gene that would have high patient applicability; (v) Development of combination therapies to address the multifactorial nature of muscular dystrophy; and (vi) Optimisation of AAV vector construct for DMD and OPMD.

We interact well with industry and have seen some of patented therapies enter clinical trial. Future projects will concentrate on further pre-clinical development of therapies not yet in trial. The project description will be geared to the applicant’s research interest and expertise.