Journal article

Amphiphilic lipopeptide significantly enhances uptake of charge-neutral splice switching morpholino oligonucleotide in spinal muscular atrophy patient-derived fibroblasts

Behnoosh Tajik-Ahmadabad, Anastasios Polyzos, Frances Separovic, Fazel Shabanpoor



Splice-switching antisense oligonucleotides (SSOs) are emerging therapeutics with two SSOs recently approved by the FDA for Duchenne muscular dystrophy and spinal muscular atrophy. SSOs are administered without any delivery vector and require large doses to achieve the therapeutic benefit, primarily due to their poor cellular uptake. Although cell-penetrating peptides (CPP) have shown great potential in delivering SSOs into cells, their capacity as delivery vector is limited. Here we have studied the effect of lipid conjugation on the cell permeability of a known CPP (ApoE). Myristic acid was coupled at the N-terminus of ApoE to a C-terminal cysteine residue. The myristoylated ApoE (Myr-ApoE..

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Awarded by Bethlehem Griffith Research Foundation grant

Funding Acknowledgements

B.T.-A. acknowledges award of a University of Melbourne-CSIRO PhD scholarship. The authors wish to thank the Biological Electron Microscopy Facility at CSIRO, particularly Dr Jacinta White for her assistance with Cryo-TEM imaging. We also acknowledge Dr Thomas Meikle (RMIT University) for his assistance with the SAXS experiments. This work was performed in part at the Materials Characterisation and Fabrication Platform (MCFP) and the Victorian Node of the Australian National Fabrication Facility (ANFF) at the University of Melbourne. Work in the laboratory of F.S was supported by the Bethlehem Griffith Research Foundation grant (BGRF1501).