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Nanotechnology approaches for inhalation treatment of fibrosis.

Savla R, Minko T - J Drug Target (2013)

Bottom Line: The mutation results in the accumulation of viscous mucus in multiple organs especially in the lungs, liver and pancreas.High associated morbidity and mortality is caused by CF due to the lack of effective therapies.Second, local lung delivery substantially prevents the penetration of the delivered drug into the systemic circulation limiting adverse side effects of the treatment on other organs and tissues.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey , Piscataway, NJ , USA.

ABSTRACT
Cystic fibrosis (CF) is an autosomal recessive monogenetic disease that afflicts nearly 70,000 patients worldwide. The mutation results in the accumulation of viscous mucus in multiple organs especially in the lungs, liver and pancreas. High associated morbidity and mortality is caused by CF due to the lack of effective therapies. It is widely accepted that morbidity and mortality caused by CF is primarily due to the respiratory manifestations of the disease. Consequently, several approaches were recently developed for treatment of lung complications of CF. However, the lack of effective methods for delivery and especially targeted delivery of therapeutics specifically to lung tissues and cells limits the efficiency of the therapy. Local pulmonary delivery of therapeutics has two major advantages over systemic application. First, it enhances the accumulation of therapeutics specifically in the lungs and therefore increases the efficiency of the treatment. Second, local lung delivery substantially prevents the penetration of the delivered drug into the systemic circulation limiting adverse side effects of the treatment on other organs and tissues. This review is focused on different approaches to the treatment of respiratory manifestations of CF as well as on methods of pulmonary delivery of therapeutics.

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The combination of cationic liposome (GL67A) and plasmid DNA expressing CFTR (pGM169). (A) pGM169 plasmid encoding the gene for CFTR protein contains no CpG dinucleotides, which are unmethylated in bacterial derived plasmids and induce inflammatory response. The plasmid also includes a CMV promoter, which aids in increased gene expression. (B) Electron microscope image of pGM169-GL67A liposomal complex. Modified from http://www.genemedresearch.ox.ac.uk/ukcfgtc/product.html.
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f6: The combination of cationic liposome (GL67A) and plasmid DNA expressing CFTR (pGM169). (A) pGM169 plasmid encoding the gene for CFTR protein contains no CpG dinucleotides, which are unmethylated in bacterial derived plasmids and induce inflammatory response. The plasmid also includes a CMV promoter, which aids in increased gene expression. (B) Electron microscope image of pGM169-GL67A liposomal complex. Modified from http://www.genemedresearch.ox.ac.uk/ukcfgtc/product.html.

Mentions: The biggest trial for non-viral gene therapy for CF is being sponsored by the UK CF Gene Therapy Consortium. A plasmid encoding the CFTR protein (pGM169) was delivered by cationic liposomes [47,48] (Figure 6). The pGM169 plasmid is under the control of the hybrid elongation factor 1α promoter and contains no CpG islands, which can cause inflammation [49]. Pringle et al. [50] showed that incorporation of a murine cytomegalovirus (CMV) enhancer in the plasmid resulted in higher transfection efficacy when compared with human CMV enhancer. In a mouse model, CFTR gene expression was registered 4 weeks after a single dose treatment. Previous pre-clinical evaluation of aerosol delivery to sheep lung demonstrated that the GL67A liposomes induced the highest gene expression when compared with 25 kDa-branched polyethyleneimine (PEI) and compacted DNA nanoparticle with polyethylene glycol (PEG)-substituted lysine 30-mer [51].Figure 6.


Nanotechnology approaches for inhalation treatment of fibrosis.

Savla R, Minko T - J Drug Target (2013)

The combination of cationic liposome (GL67A) and plasmid DNA expressing CFTR (pGM169). (A) pGM169 plasmid encoding the gene for CFTR protein contains no CpG dinucleotides, which are unmethylated in bacterial derived plasmids and induce inflammatory response. The plasmid also includes a CMV promoter, which aids in increased gene expression. (B) Electron microscope image of pGM169-GL67A liposomal complex. Modified from http://www.genemedresearch.ox.ac.uk/ukcfgtc/product.html.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4219586&req=5

f6: The combination of cationic liposome (GL67A) and plasmid DNA expressing CFTR (pGM169). (A) pGM169 plasmid encoding the gene for CFTR protein contains no CpG dinucleotides, which are unmethylated in bacterial derived plasmids and induce inflammatory response. The plasmid also includes a CMV promoter, which aids in increased gene expression. (B) Electron microscope image of pGM169-GL67A liposomal complex. Modified from http://www.genemedresearch.ox.ac.uk/ukcfgtc/product.html.
Mentions: The biggest trial for non-viral gene therapy for CF is being sponsored by the UK CF Gene Therapy Consortium. A plasmid encoding the CFTR protein (pGM169) was delivered by cationic liposomes [47,48] (Figure 6). The pGM169 plasmid is under the control of the hybrid elongation factor 1α promoter and contains no CpG islands, which can cause inflammation [49]. Pringle et al. [50] showed that incorporation of a murine cytomegalovirus (CMV) enhancer in the plasmid resulted in higher transfection efficacy when compared with human CMV enhancer. In a mouse model, CFTR gene expression was registered 4 weeks after a single dose treatment. Previous pre-clinical evaluation of aerosol delivery to sheep lung demonstrated that the GL67A liposomes induced the highest gene expression when compared with 25 kDa-branched polyethyleneimine (PEI) and compacted DNA nanoparticle with polyethylene glycol (PEG)-substituted lysine 30-mer [51].Figure 6.

Bottom Line: The mutation results in the accumulation of viscous mucus in multiple organs especially in the lungs, liver and pancreas.High associated morbidity and mortality is caused by CF due to the lack of effective therapies.Second, local lung delivery substantially prevents the penetration of the delivered drug into the systemic circulation limiting adverse side effects of the treatment on other organs and tissues.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey , Piscataway, NJ , USA.

ABSTRACT
Cystic fibrosis (CF) is an autosomal recessive monogenetic disease that afflicts nearly 70,000 patients worldwide. The mutation results in the accumulation of viscous mucus in multiple organs especially in the lungs, liver and pancreas. High associated morbidity and mortality is caused by CF due to the lack of effective therapies. It is widely accepted that morbidity and mortality caused by CF is primarily due to the respiratory manifestations of the disease. Consequently, several approaches were recently developed for treatment of lung complications of CF. However, the lack of effective methods for delivery and especially targeted delivery of therapeutics specifically to lung tissues and cells limits the efficiency of the therapy. Local pulmonary delivery of therapeutics has two major advantages over systemic application. First, it enhances the accumulation of therapeutics specifically in the lungs and therefore increases the efficiency of the treatment. Second, local lung delivery substantially prevents the penetration of the delivered drug into the systemic circulation limiting adverse side effects of the treatment on other organs and tissues. This review is focused on different approaches to the treatment of respiratory manifestations of CF as well as on methods of pulmonary delivery of therapeutics.

Show MeSH
Related in: MedlinePlus