Journal article
Splice modulating antisense oligonucleotides restore some acid-alpha-glucosidase activity in cells derived from patients with late-onset Pompe disease
Scientific Reports, Vol.10, Article number: 6702
2020
Abstract
Pompe disease is caused by mutations in the GAA gene, resulting in deficient lysosomal acid-α-glucosidase activity in patients, and a progressive decline in mobility and respiratory function. Enzyme replacement therapy is one therapeutic option, but since not all patients respond to this treatment, alternative interventions should be considered. One GAA mutation, c.-32-13T > G, impacts upon normal exon 2 splicing and is found in two-thirds of late-onset cases. We and others have explored a therapeutic strategy using splice modulating phosphorodiamidate morpholino oligomers to enhance GAA exon 2 inclusion in the mature mRNA of patients with one c.-32-13T > G allele. We designed 20 oligomers and treated fibroblasts derived from five patients to identify an oligomer sequence that maximally increased enzyme activity in all fibroblasts. The most effective splice correcting oligomer was chosen to treat forced-myogenic cells, derived from fibroblasts from nine patients carrying the c.-32-13T > G mutation. After transfection, we show increased levels of the full-length GAA transcript, acid-α-glucosidase protein, and enzyme activity in all patients’ myogenic cells, regardless of the nature of the mutation in the other allele. This data encourages the initiation of clinical trials to assess the therapeutic efficacy of this oligomer for those patients carrying the c.-32-13T > G mutation.
Details
- Title
- Splice modulating antisense oligonucleotides restore some acid-alpha-glucosidase activity in cells derived from patients with late-onset Pompe disease
- Authors/Creators
- M.T. Aung-Htut (Author/Creator) - Murdoch UniversityK.A. Ham (Author/Creator) - Murdoch UniversityM. Tchan (Author/Creator) - Westmead HospitalR. Johnsen (Author/Creator) - Murdoch UniversityF.J. Schnell (Author/Creator) - Sarepta Therapeutics (United States)S. Fletcher (Author/Creator) - Murdoch UniversityS.D. Wilton (Author/Creator) - Murdoch University
- Publication Details
- Scientific Reports, Vol.10, Article number: 6702
- Publisher
- Nature Research
- Identifiers
- 991005540863207891
- Copyright
- © The Author(s) 2020
- Murdoch Affiliation
- Centre for Molecular Medicine and Innovative Therapeutics
- Language
- English
- Resource Type
- Journal article
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- Collaboration types
- Industry collaboration
- Domestic collaboration
- International collaboration
- Citation topics
- 1 Clinical & Life Sciences
- 1.271 Lysosomal Storage Disorders
- 1.271.673 Enzyme Replacement Therapy
- Web Of Science research areas
- Genetics & Heredity
- ESI research areas
- Molecular Biology & Genetics