Gene Therapy for Pulmonary Diseases

Kolb, Martin; Martin, Gail; Medina, Maria Fe C.; Ask, Kjetil; Gauldie, Jack

doi:10.1378/chest.130.3.879

Cited by 52 publications

(36 citation statements)

References 33 publications

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“…This suggests that even modest levels of CFTR gene transfer throughout the airways, rather than a high level of spatially confined transgene expression, may be required to restore the defects in CF lungs. Moreover, thanks to the identification of genetic targets, the ability to achieve widespread transgene expression may provide therapeutic breakthroughs for diseases such as COPD and asthma that affect both airways and lung parenchyma (55,56). We subsequently investigated whether the ability of PBAEMPPs to penetrate the mucus layer and reach the underlying epithelium enhances the overall gene transfer efficacy following intratracheal administration.…”

Section: Resultsmentioning

confidence: 99%

Highly compacted biodegradable DNA nanoparticles capable of overcoming the mucus barrier for inhaled lung gene therapy

Mastorakos

Silva

Chisholm

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

171

151

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Gene therapy has emerged as an alternative for the treatment of diseases refractory to conventional therapeutics. Synthetic nanoparticle-based gene delivery systems offer highly tunable platforms for the delivery of therapeutic genes. However, the inability to achieve sustained, high-level transgene expression in vivo presents a significant hurdle. The respiratory system, although readily accessible, remains a challenging target, as effective gene therapy mandates colloidal stability in physiological fluids and the ability to overcome biological barriers found in the lung. We formulated highly stable DNA nanoparticles based on state-of-theart biodegradable polymers, poly(β-amino esters) (PBAEs), possessing a dense corona of polyethylene glycol. We found that these nanoparticles efficiently penetrated the nanoporous and highly adhesive human mucus gel layer that constitutes a primary barrier to reaching the underlying epithelium. We also discovered that these PBAE-based mucus-penetrating DNA nanoparticles (PBAE-MPPs) provided uniform and high-level transgene expression throughout the mouse lungs, superior to several gold standard gene delivery systems. PBAE-MPPs achieved robust transgene expression over at least 4 mo following a single administration, and their transfection efficiency was not attenuated by repeated administrations, underscoring their clinical relevance. Importantly, PBAE-MPPs demonstrated a favorable safety profile with no signs of toxicity following intratracheal administration.lung gene therapy | mucus-penetrating particles | nanotechnology | biodegradable polymer | nonviral gene delivery

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Section: Resultsmentioning

confidence: 99%

Highly compacted biodegradable DNA nanoparticles capable of overcoming the mucus barrier for inhaled lung gene therapy

Mastorakos

Silva

Chisholm

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

171

151

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“…Böylelikle vektöre ihtiyaç duymadan gen tedavisi mümkün olabilmektedir. 56,57 3) Heparin: Kuru toz düşük moleküler ağırlıklı inhale heparin formunun inhaler heparin formuna göre daha iyi absorbe olduğu gözlenmiştir. Heparinin antiinflamatuar, antinötrofil elastaz ve mukokinetik özellikleri vardır.…”

Section: ) Gen Terapi Vektörleri (Cftr-avv)unclassified

Inhaled Therapy in Children

Pekcan¹

2012

Solunum

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“…The transfer of genes to the airway results in gene expression primarily in lung epithelial cells, and the transgene is localised to the lung without much systemic distribution. The highest level of CFTR gene expression is found in the bronchial submucosal gland cells (Merten et al, 1996;Kammouni et al, 1999;Chow et al, 2000) and it was suggested that these glandular cells may be better reached by vasculature and systemic application of the vector rather than by the airways (Boucher, 1999 ;Kolb et al, 2006).…”

Section: Cftr Gene Transfer To the Airway Epitheliummentioning

confidence: 99%