Current status of non-viral gene therapy for CNS disorders

Abstract

Introduction: Viral and non-viral vectors have been used as methods of delivery in gene therapy for many CNS diseases. Currently, viral vectors such as adeno-associated viruses (AAV), retroviruses, lentiviruses, adenoviruses and herpes simplex viruses (HHV) are being used as successful vectors in gene therapy at clinical trial levels. However, many disadvantages have risen from their usage. Non-viral vectors like cationic polymers, cationic lipids, engineered polymers, nanoparticles, and naked DNA offer a much safer option and can therefore be explored for therapeutic purposes.

Areas covered: This review discusses different types of viral and non-viral vectors for gene therapy and explores clinical trials for CNS diseases that have used these types of vectors for gene delivery. Highlights include non-viral gene delivery and its challenges, possible strategies to improve transfection, regulatory issues concerning vector usage, and future prospects for clinical applications.

Expert opinion: Transfection efficiency of cationic lipids and polymers can be improved through manipulation of molecules used. Efficacy of cationic lipids is dependent on cationic charge, saturation levels, and stability of linkers. Factors determining efficacy of cationic polymers are total charge density, molecular weights, and complexity of molecule. All of the above mentioned parameters must be taken care for efficient gene delivery.

Keywords: Gene delivery; brain delivery; central nervous system; nanobiotechnology; neurological disorders; viral/non-viral vector.

Figure 1

Types of gene delivery systems.

Figure 2. Schematic representation of gene delivery mechanism

Upon assembly of the selected nucleic acid cargo with the delivery vector construct, the composite particles (e.g. lipoplex or polyplex) must traverse various extracellular barrier (e.g., serum endonucleases) followed by cellular entry via endocytosis or by other biological means. Following uptake, gene particles modulate gene expression either in the cytosol (expression independent) or in the nucleus (expression dependent){Reproduce with permission [32]}.

Figure 3

Indications addressed by gene therapy clinical trials (adapted from http://www.wiley.co.uk/genmed/clinical) [38] and data obtained from www.clinicaltrails.gov.

Figure 4

Schematic representation of different type of polymeric materials and nanocarriers used in the nonviral gene delivery systems.

Figure 5

Barriers faced by non-viral gene therapies following systematic delivery. {Reproduce with permission from [68]}