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

Tony Le Gall,Pierre Lehn,Mathieu Berchel,Steve Hyde,Paul-Alain Jaffrès,Jean-Marie Lehn,Bruno Pitard,Deborah Gill,Tristan Montier,Loïc Lemiègre,Rosy Ghanem,Alain Fautrel,Lee Davies,Angélique Mottais,Thierry Benvegnu

doi:10.3390/pharmaceutics14010025

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.

Highlights

IntroductionNebulization to the lung airways is an attractive, clinically-relevant, administration method, especially because high loads of active drug can be directly delivered to the Pharmaceutics 2022, 14, 25
They were used to prepare a series of lipidic formulations using GL67A composition as a guide, assuming that the parameters identified as optimal for GL67 would be similar for other related lipid-based formulations
The possibility to prepare such formulations at high concentrations was first determined. Those for which this was feasible were mixed with plasmid DNA (pDNA) to obtain concentrated lipoplexes, which were mostly characterized with a charge ratio and a PEGylation ratio similar that of GL67A-based lipoplexes

Summary

Introduction

Nebulization to the lung airways is an attractive, clinically-relevant, administration method, especially because high loads of active drug can be directly delivered to the Pharmaceutics 2022, 14, 25. It is suitable to treat various respiratory diseases, notably cystic fibrosis (CF; OMIM 219700; one of the most prevalent genetic diseases in Caucasian populations). The latter is a life-threatening autosomal recessive disorder that has a prognosis closely associated with the respiratory failure it causes [1]. The airway delivery route faces specific obstacles, stimulating research focusing on both the inhalation method [6] and the therapeutic treatment to be delivered [7,8,9]

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Discussion

Conclusion