Aerosol-Mediated Non-Viral Lung Gene Therapy: The Potential of Aminoglycoside-Based Cationic Liposomes

Abstract

Aerosol lung gene therapy using non-viral delivery systems represents a credible therapeutic strategy for chronic respiratory diseases, such as cystic fibrosis (CF). Progress in CF clinical setting using the lipidic formulation GL67A has demonstrated the relevance of such a strategy while emphasizing the need for more potent gene transfer agents. In recent years, many novel non-viral gene delivery vehicles were proposed as potential alternatives to GL67 cationic lipid. However, they were usually evaluated using procedures difficult or even impossible to implement in clinical practice. In this study, a clinically-relevant administration protocol via aerosol in murine lungs was used to conduct a comparative study with GL67A. Diverse lipidic compounds were used to prepare a series of formulations inspired by the composition of GL67A. While some of these formulations were ineffective at transfecting murine lungs, others demonstrated modest-to-very-efficient activities and a series of structure-activity relationships were unveiled. Lipidic aminoglycoside derivative-based formulations were found to be at least as efficient as GL67A following aerosol delivery of a luciferase-encoding plasmid DNA. A single aerosol treatment with one such formulation was found to mediate long-term lung transgene expression, exceeding half the animal’s lifetime. This study clearly supports the potential of aminoglycoside-based cationic lipids as potent GL67-alternative scaffolds for further enhanced aerosol non-viral lung gene therapy for diseases such as CF.

Ruthenium(II) Polypyridyl Complexes for Antimicrobial Photodynamic Therapy: Prospects for Application in Cystic Fibrosis Lung Airways

“…CF lung disease could be eligible for treatment with aPDT for several reasons, including the following. (i) Lung airways can be targeted with a local administration method, especially via aerosol that allows one to obtain a high load of in situ active drugs with low systemic side-effects [50][51][52]. (ii) Because PDT reactions only occur in areas where the PS accumulates and light is applied, lung pathogens settling at the epithelium surface can be the first biological targets of PDT-induced oxidative stresses.…”

Screening Libraries to Discover Molecular Design Principles for the Targeted Delivery of mRNA with One-Component Ionizable Amphiphilic Janus Dendrimers Derived from Plant Phenolic Acids

“…These results also represent a first step towards the generation of a nanoperiodic table of IAJDs for the delivery of mRNA, similar to those of proteins [ 261 , 262 , 263 ], self-assembling dendrons, and dendrimers [ 198 , 264 , 265 ], that may be able to help expand the fields of genetic medicine and nanomedicine [ 34 , 266 , 267 , 268 , 269 ].…”

Oral Delivery of miR-320-3p with Lipidic Aminoglycoside Derivatives at Mid-Lactation Alters miR-320-3p Endogenous Levels in the Gut and Brain of Adult Rats According to Early or Regular Weaning

“…Such a vector would help resolve the paradox of a gut delivery with consequences in the brain area on the levels of endogenous miR-320-3p or miR-375-3p. The delivery of miRNAs with lipidic aminoglycosides can be added to the nanoparticles industrially available [41]; their main advantage over exosomes is that the loading is easy and reliable [36,42]. miR-320-3p is present in breast milk exosomes, but there is no report on any effect of this miRNA on the homeostasis of pups (being loaded in exosomes or lipoprotein complexes as reviewed by Groot and Lee (2020) [43]).…”

“…Therefore, in the present study, we aimed to investigate the effects of the artificial delivery of microRNAs naturally present in breastmilk on the gut and brain of young rats following early life stress. For their delivery, we used previously developed lipidic derivatives of natural aminoglycosides-allowed in food-that have been shown to efficiently deliver siRNA, DNA, mRNA, or miRNA to cells [20,[32][33][34][35][36]. Lipidic aminoglycosides are used to embed RNA molecules diluted in a physiological buffer within minutes at room temperature, right before oral administration [20,35].…”