Inhaled gene delivery: a formulation and delivery approach

ABSTRACT

Introduction: Gene therapy is a potential alternative to treat a number of diseases. Different hurdles are associated with aerosol gene delivery due to the susceptibility of plasmid DNA (pDNA) structure to be degraded during the aerosolization process. Different strategies have been investigated in order to protect and efficiently deliver pDNA to the lungs using non-viral vectors. To date, no successful therapy involving non-viral vectors has been marketed, highlighting the need for further investigation in this field.

Areas covered: This review is focused on the formulation and delivery of DNA to the lungs, using non-viral vectors. Aerosol gene formulations are divided according to the current delivery systems for the lung: nebulizers, dry powder inhalers and pressurized metered dose inhalers; highlighting its benefits, challenges and potential application.

Expert opinion: Successful aerosol delivery is achieved when the supercoiled DNA structure is protected during aerosolization. A formulation strategy or compounds that can protect, stabilize and efficiently transfect DNA into the cells is desired in order to produce an effective, low-cost and safe formulation. Nebulizers and dry powder inhalers are the most promising approaches to be used for aerosol delivery, due to the lower shear forces involved. In this context it is also important to highlight the importance of considering the ‘pDNA-formulation-device system’ as an integral part of the formulation development for a successful nucleic acid delivery.

KEYWORDS:

• Non-viral
• DNA
• nebulizer
• dry powder inhaler (DPI)
• pressurized metered dose inhaler (pMDI)

Article Highlights

• The use of non-viral vectors to deliver pDNA is an alternative to produce a low cost, safe and efficient gene delivery.

• The lung is a potential route for administering nucleic acids due to its lower nuclease activity compared to the blood stream, rapid absorption and potential to treat local and systemic diseases.

• The lack of vectors and formulations that can efficiently deliver pDNA is the main limiting step in the production of an effective treatment.

• The degradation or disruption of pDNA structure is still the main obstacle for gene therapy to the lung.

• Choosing the right combination of device and formulation for the protection of the supercoiled (sc) structure of pDNA in aerosol delivery is of fundamental importance.

• The different inhaler devices (nebulizers, DPI and pMDI) and formulations studied in gene delivery using non-viral vectors are presented.

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Declaration of interest

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Additional information

Funding

The authors thank the CAPES Foundation, Ministry of Education of Brazil for the financial support of L Gomes dos Reis. P Young is the recipient of an Australian Research Council Future Fellowship (project number FT110100996). D Traini is the recipient of an Australian Research Council Future Fellowship (project number FT12010063).