Pulmonary delivery of sirna for the treatment of cystic fibrosis and pulmonary delivery platforms

Cystic fibrosis (CF) is one of the most deadly diseases of lungs that involves symptoms such as breathing difficulties, coughing and lung infection. Despite important therapeutic advances, the definitive treatment for CF remains elusive. CF is a good candidate for gene therapy because it is relatively common, lethal and monogenic and it does not have adequate treatment options. In this review article, we have reviewed gene therapy as a potential treatment option for CF. Various platforms and strategies for pulmonary gene delivery have also been discussed in detail.

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Gene delivery systems—gene therapy vectors for cystic fibrosis

Journal of Cystic Fibrosis ◽

10.1016/j.jcf.2004.05.042 ◽

2004 ◽

Vol 3 ◽

pp. 203-212 ◽

Cited By ~ 20

Author(s):

Daniel Klink ◽

Dirk Schindelhauer ◽

Andreas Laner ◽

Torry Tucker ◽

Zsuzsanna Bebok ◽

...

Keyword(s):

Cystic Fibrosis ◽

Gene Therapy ◽

Gene Delivery ◽

Delivery Systems ◽

Gene Therapy Vectors

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Cystic fibrosis lung disease following infection with Pseudomonas aeruginosa in Cftr knockout mice using novel non-invasive direct pulmonary infection technique

Laboratory Animals ◽

10.1258/0023677054306944 ◽

2005 ◽

Vol 39 (3) ◽

pp. 336-352 ◽

Cited By ~ 38

Author(s):

C Guilbault ◽

P Martin ◽

D Houle ◽

M-L Boghdady ◽

M-C Guiot ◽

...

Keyword(s):

Cystic Fibrosis ◽

Pseudomonas Aeruginosa ◽

Pulmonary Delivery ◽

Lung Infection ◽

Invasive Technique ◽

Non Invasive ◽

Transmembrane Channel ◽

Nutritional Conditions ◽

Cystic Fibrosis Lung Disease ◽

Delivery Technique

To better understand the mechanism of lung infection with Pseudomonas aeruginosa ( P. aeruginosa), many techniques have been developed in order to establish lung infection in rodents. A model of chronic lung infection, using tracheotomy to inoculate the bacteria, has been extensively used in the cystic fibrosis (CF) mouse model of lung infection. The cystic fibrosis transmembrane channel ( Cftr) knockout (KO) mice are smaller than normal mice and are more sensitive to housing and nutritional conditions, leading to small amounts of animals being available for experiments. Because of these characteristics, and because of the invasiveness of the infection procedure which we, and others, have been using to mimic the lung infection, we sought to find an alternative way to study the inflammatory response during lung P. aeruginosa infection. The technique we describe here consists of the injection of bacterial beads directly into the lungs through the mouth without the need of any tracheal incisions. This technique of direct pulmonary delivery enables much faster infection of the animals compared with the intratracheal technique previously used. The use of this less invasive technique allows the exclusion of the surgery-related inflammation. Our results show that, using the direct pulmonary delivery technique, the KO mice were more susceptible to P. aeruginosa lung infection compared with their wild-type (WT) controls, as shown by their increased weight loss, higher bacterial burden and more elevated polymorphonuclear (PMN) alveolar cell recruitment into the lungs. These differences are consistent with the pathological profiles observed in CF patients infected with P. aeruginosa. Overall, this method simplifies the infection procedure in terms of its duration and invasiveness, and improves the survival rate of the KO mice when compared with the previously used intratracheal procedure.

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167. Development of Non-Viral Gene Delivery Systems Deliverable Via Aerosol and Displaying Broad-Spectrum Antibacterial Activity for Cystic Fibrosis Gene Therapy

Molecular Therapy ◽

10.1016/s1525-0016(16)33772-8 ◽

2015 ◽

Vol 23 ◽

pp. S66-S67

Author(s):

Tony Le Gall ◽

Angélique Mottais ◽

Mathieu Berchel ◽

Pierre Lehn ◽

Paul-Alain Jaffres ◽

...

Keyword(s):

Cystic Fibrosis ◽

Gene Therapy ◽

Antibacterial Activity ◽

Gene Delivery ◽

Broad Spectrum ◽

Delivery Systems ◽

Cystic Fibrosis Gene ◽

Viral Gene ◽

Viral Gene Delivery

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363. Gene Delivery to Human Sweat Glands: A Model for Cystic Fibrosis Gene Therapy

Molecular Therapy ◽

10.1016/j.ymthe.2005.06.366 ◽

2005 ◽

Vol 11 ◽

pp. S142

Keyword(s):

Cystic Fibrosis ◽

Gene Therapy ◽

Gene Delivery ◽

Cystic Fibrosis Gene ◽

Sweat Glands ◽

Human Sweat

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Novel molecular approaches to cystic fibrosis gene therapy

Biochemical Journal ◽

10.1042/bj20041923 ◽

2005 ◽

Vol 387 (1) ◽

pp. 1-15 ◽

Cited By ~ 47

Author(s):

Tim W. R. LEE ◽

David A. MATTHEWS ◽

G. Eric BLAIR

Keyword(s):

Cystic Fibrosis ◽

Gene Therapy ◽

Gene Delivery ◽

Viral Vectors ◽

Bronchial Tree ◽

Endosomal Escape ◽

Host Cells ◽

Cystic Fibrosis Gene ◽

Viral Gene ◽

Molecular Approaches

Gene therapy holds promise for the treatment of a range of inherited diseases, such as cystic fibrosis. However, efficient delivery and expression of the therapeutic transgene at levels sufficient to result in phenotypic correction of cystic fibrosis pulmonary disease has proved elusive. There are many reasons for this lack of progress, both macroscopically in terms of airway defence mechanisms and at the molecular level with regard to effective cDNA delivery. This review of approaches to cystic fibrosis gene therapy covers these areas in detail and highlights recent progress in the field. For gene therapy to be effective in patients with cystic fibrosis, the cDNA encoding the cystic fibrosis transmembrane conductance regulator protein must be delivered effectively to the nucleus of the epithelial cells lining the bronchial tree within the lungs. Expression of the transgene must be maintained at adequate levels for the lifetime of the patient, either by repeat dosage of the vector or by targeting airway stem cells. Clinical trials of gene therapy for cystic fibrosis have demonstrated proof of principle, but gene expression has been limited to 30 days at best. Results suggest that viral vectors such as adenovirus and adeno-associated virus are unsuited to repeat dosing, as the immune response reduces the effectiveness of each subsequent dose. Nonviral approaches, such as cationic liposomes, appear more suited to repeat dosing, but have been less effective. Current work regarding non-viral gene delivery is now focused on understanding the mechanisms involved in cell entry, endosomal escape and nuclear import of the transgene. There is now increasing evidence to suggest that additional ligands that facilitate endosomal escape or contain a nuclear localization signal may enhance liposome-mediated gene delivery. Much progress in this area has been informed by advances in our understanding of the mechanisms by which viruses deliver their genomes to the nuclei of host cells.

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Optimizations of In Vitro Mucus and Cell Culture Models to Better Predict In Vivo Gene Transfer in Pathological Lung Respiratory Airways: Cystic Fibrosis as an Example

Pharmaceutics ◽

10.3390/pharmaceutics13010047 ◽

2020 ◽

Vol 13 (1) ◽

pp. 47

Author(s):

Rosy Ghanem ◽

Véronique Laurent ◽

Philippe Roquefort ◽

Tanguy Haute ◽

Sophie Ramel ◽

...

Keyword(s):

Cystic Fibrosis ◽

Gene Therapy ◽

Cell Culture ◽

Gene Transfer ◽

Gene Delivery ◽

Culture Models ◽

Transfer Strategies ◽

Cell Culture Models

The respiratory epithelium can be affected by many diseases that could be treated using aerosol gene therapy. Among these, cystic fibrosis (CF) is a lethal inherited disease characterized by airways complications, which determine the life expectancy and the effectiveness of aerosolized treatments. Beside evaluations performed under in vivo settings, cell culture models mimicking in vivo pathophysiological conditions can provide complementary insights into the potential of gene transfer strategies. Such models must consider multiple parameters, following the rationale that proper gene transfer evaluations depend on whether they are performed under experimental conditions close to pathophysiological settings. In addition, the mucus layer, which covers the epithelial cells, constitutes a physical barrier for gene delivery, especially in diseases such as CF. Artificial mucus models featuring physical and biological properties similar to CF mucus allow determining the ability of gene transfer systems to effectively reach the underlying epithelium. In this review, we describe mucus and cellular models relevant for CF aerosol gene therapy, with a particular emphasis on mucus rheology. We strongly believe that combining multiple pathophysiological features in single complex cell culture models could help bridge the gaps between in vitro and in vivo settings, as well as viral and non-viral gene delivery strategies.

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