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.

Chitosan-Shelled Nanobubbles Irreversibly Encapsulate Morpholino Conjugate Antisense Oligonucleotides and Are Ineffective for Phosphorodiamidate Morpholino-Mediated Gene Silencing of DUX4

Argenziano, M
Co-first
;
Cavalli, R;
2021-01-01

Abstract

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.
2021
31
3
201
207
PMO AON; FSHD; nanobubbles; DUX4silencing
Falzarano, MS; Argenziano, M; Marsollier, AC; Mariot, V; Rossi, D; Selvatici, R; Dumonceaux, J; Cavalli, R; Ferlini, A
File in questo prodotto:
File Dimensione Formato  
Falzarano_et_al._NAT_2020.docx

Accesso riservato

Tipo di file: PREPRINT (PRIMA BOZZA)
Dimensione 46.57 kB
Formato Microsoft Word XML
46.57 kB Microsoft Word XML   Visualizza/Apri   Richiedi una copia
Falzarano_et_al._NAT_2020.pdf

Accesso aperto

Tipo di file: PREPRINT (PRIMA BOZZA)
Dimensione 202.5 kB
Formato Adobe PDF
202.5 kB Adobe PDF Visualizza/Apri

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2318/1772923
Citazioni
  • ???jsp.display-item.citation.pmc??? 8
  • Scopus 11
  • ???jsp.display-item.citation.isi??? 10
social impact