Aerosol Delivery of Gene Therapeutics to the Lung

A Next Generation Cascade Impactor (NGI). Used for measuring the droplet sizes in aerosol formulations.


Gene therapies utilizing modified viruses or plasmid DNA (pDNA) to re-introduce functional copies of defective or mutated genes are being investigated for the treatment of a wide range of lung diseases including cystic fibrosis (CF), cancer and alpha-1 anti-trypsin deficiency (Gill et al., 2004). The relative accessibility of the pulmonary epithelium makes aerosol delivery of gene therapy formulations an attractive possibility, allowing non-invasive application to target cells within the lung whilst minimising the risks associated with systemic delivery. Following identification of the gene responsible for CF in 1989 (Riordan et al., 1989) the disease has served as a paradigm for gene therapy in general and aerosol gene therapy in particular. To date there have been a total of 26 Phase I/II gene therapy clinical trials for CF including 8 trials incorporating aerosol delivery (of gene transfer agents) to the lungs of CF patients as a key component of the study (Griesenbach et al., 2009).


Present state of art

Although the field of gene therapy proceeds at pace, transfer of technological developments to aerosol gene therapy has been limited by the additional constraints placed upon formulations for nebulization and the associated costs of developing and testing aerosol formulations in relevant animal model systems. To date only 3 gene transfer agents, recombinant adenovirus (Ad) (Perricone et al., 2001), adeno-associated virus (AAV) (Moss et al., 2007) and pDNA complexed to the cationic lipid Genzyme Lipid 67A (GL67A) (Alton et al., 1999) have been aerosolised to the lungs of patients and whilst a huge variety of gene transfer agents is now available, few have proven suitable for aerosolization. A recent study by the UK CF Gene Therapy Consortium identified shear related degradation of pDNA during nebulization as the primary limitation in the progression of novel non-viral gene therapy formulations towards the clinic, with only 10% of tested formulations demonstrating efficacy following jet nebulization. Consequently, potential aerosol gene therapy applications are currently severely limited both by the choice of suitable vectors and available delivery devices.
Evidence from in vivo studies and human clinical trials has indicated that lung gene transfer mediated commitment  by aerosolizable vectors remains inefficient and gene expression is transient in nature (Rochat et al., 2002). As a result, it is likely that repeated administration of costly gene therapy formulations will be required to observe clinical benefit. Such requirements will have significant impact upon patient compliance and the overall cost of any future gene therapy applications.

What remains to be done

An Aerotech II nebuliser generating a PEI/pDNA aerosol.

Despite considerable advances in the field of aerosol gene therapy it remains clear that current gene transfer agents are inefficient for lung gene transfer and considerable advances will be required before viable clinical aerosol applications are achieved. Optimisation of gene transfer agents to generate persistent high-level gene expression in the lung will be of significant benefit although identification of physical and molecular barriers to gene transfer in the lung are likely to prove equally critical. It is also essential that suitable nebulization devices are available to deliver formulations efficiently and without deleterious effects upon the delivered formulations.


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