Journal
NUCLEIC ACID THERAPEUTICS
Volume 31, Issue 3, Pages 201-207Publisher
MARY ANN LIEBERT, INC
DOI: 10.1089/nat.2020.0862
Keywords
PMO AON; FSHD; nanobubbles; DUX4silencing
Funding
- FSHD society grant [FSHS-22018-02]
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While nanocarriers are considered promising for drug delivery, experiments showed that chitosan-shelled NBs are not ideal for PMO AON-related therapies due to lack of therapeutic effect in suppressing target gene expression.
Orphan drugs, including antisense oligonucleotides (AONs), siRNAs/miRNAs, Cas9 nuclease, and recombinant genes, have recently been made available for rare diseases. However, the main bottleneck for these new therapies is delivery. Drugs/synthetic genes need to reach the affected tissues with minimal off-target effects and immune reactions. AON molecules are currently delivered as backboned naked compounds or via viral vectors. Nanocarriers are considered promising vehicles, able to improve drug distribution by organ targeting and limiting safety issues. We tested perfluoropentane-based nanobubbles (NBs) as vehicles for loading phosphorodiamidate morpholino (PMO) AON to suppress DUX4 expression in a facioscapulohumeral muscular dystrophy cell model.In vitrocell-free analysis demonstrated a good loading capacity of PMO into NBs, while experiments in cell cultures showed lack of therapeutic effect since expression of DUX4 and its targets remained unmodified. We conclude that these types of chitosan-shelled NBs do not release PMO-AON and are therefore not ideal for PMO AON-related therapies.
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