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Targeted gene delivery and Cystic Fibrosis

The previous article eloquently highlights the advances in targeting gene delivery over the last couple of decades. Part of the challenge of targeting gene delivery lies in the individual cell and tissue environments which need to be targeted in different diseases. Recent studies have addressed the issue of target gene delivery to the lung for potentially targeted treatment of diseases such as Cystic Fibrosis (CF). CF is a devastating autosomal recessively inherited genetic disease that affects most notably the lungs, but also the liver, pancreas and intestines. It involves a defect in epithelial transport of sodium and chlorine and is caused by mutations in the CFTR gene. The aim of gene therapy in CF would be to introduce a normal copy of the CFTR gene into cells. However, the field has been fraught with difficulties including poor vector take-up by cell and problems with humoral immunity associated with adenoviral vectors.

However, there have been some promising results. In a study from the Univeristy of Florida, a CFTR knockout mouse model of a IgE-mediated hypersensitivity (allergic bronchopulmonary aspergillosis (ABPA))syndrome which occurs in approximately 15% of CF patients was studied. A truncated CFTR was delivered to mouse airway epiltelium via intra-tracheal (IT) delivery of recombinant adeno-associated virus and was found to attenuate the hyper-IgE response. However, more recent studies have focused on non-viral gene delivery systems such as the nanoparticles referred to in the previous article. Chitosan is a polysaccharide whose properties have led to its use drug delivery systems.Guanidinylated chitosan (GCS) has been developed as a non-viral vector termed the chitosan-derived nanodelivery vehicle (SGCS), that can be used to deliver nanoparticles to lung cells. This was recently shown to successfully deliver siRNA to lung cells. In another example, chitosan-DNA-FAP-B nanoparticles were identified as novel non-viral vectors for specific gene delivery to lung epithelial cells. They were effective in targeted gene delivery to fibronectin molecules of lung epithelial cell membrane and can be delivered by aerosol to give several-fold greater gene expression in mice lungs compared with Chitosan-DNA nanoparticles. Chitosan-DNA nanoparticles can also be effectively delivered to liver cells in mice, which has further relevance for CF.

Studies on naonparticle delivery are focusing on factors such as cytotoxicity and effectiveness of delivery via aerosol. The chitosan-based vectors may be a promising avenue for further development in gene therapy for diseases such as CF.

Sources

DAI, H. et al., 2006. Chitosan-DNA nanoparticles delivered by intrabiliary infusion enhance liver-targeted gene delivery. International Journal Of Nanomedicine, 1(4), pp. 507-522

FLOTTE, T.R. and LAUBE, B.L., 2001. Gene therapy in cystic fibrosis. Chest, 120(3), pp. 124S-131S

LUO, Y. et al., 2012. An inhalable ß2-adrenoceptor ligand-directed guanidinylated chitosan carrier for targeted delivery of siRNA to lung. Journal Of Controlled Release: Official Journal Of The Controlled Release Society, 162(1), pp. 28-36

MOHAMMADI, Z. et al., 2011. In vivo transfection study of chitosan-DNA-FAP-B nanoparticles as a new non viral vector for gene delivery to the lung. International journal of pharmaceutics, 421(1), pp. 183-188

MOHAMMADI, Z. et al., 2012. Stability studies of chitosan-DNA-FAP-B nanoparticles for gene delivery to lung epithelial cells. Acta Pharmaceutica (Zagreb, Croatia), 62(1), pp. 83-92

MUELLER, C. et al., 2008. Partial correction of the CFTR-dependent ABPA mouse model with recombinant adeno-associated virus gene transfer of truncated CFTR gene. The journal of gene medicine, 10(1), pp. 51-60

YEO, Y., 2010. Battling with environments: drug delivery to target tissues with particles and functional biomaterials. Therapeutic Delivery, 1(6), pp. 757-761