Delivery systems for gene therapy should be tailored to the particular disease studied. Although cell-specific targeting and prolonged gene expression are, in general, primary goals for gene transfer, situations can be envisioned in which less stringent requirements would be acceptable or even preferable. Thus, transient expression and/or neighboring approaches might be chosen over long-term and/or direct cell targeting. Each delivery system has advantages and disadvantages, and it is likely that no one vector is ideal for all strategies. Differences include tissue tropism, length of gene expression, vector carrying capacity, the potential for integration into the genome, generation of immune responses, and toxicity.
Appropriate target structures or cell types for glaucoma gene therapy include trabecular meshwork (TM), ciliary epithelium (CE), ciliary muscle (CM), RGCs, and Müller cells (MCs). The TM, located at the iridocorneal angle, is a spongiform tissue formed by different endothelial cells and extracellular matrix arranged in a particular architecture. It is the tissue responsible for maintaining the resistance to aqueous humor flow and keeping the ocular globe inflated. The CE is formed of two, intimately connected cell layers covering the ciliary processes. The outer layer facing the posterior chamber is nonpigmented, and it is responsible for the secretion of aqueous humor. Once secreted, the aqueous humor flows around the iris to the anterior chamber and leaves the eye through the cells of the TM and inner wall of Schlemm’s canal to the venous system. The CM lies close to the CE and the TM. When the CM contracts, it provides lens accommodation and changes in the configuration of the TM, facilitating the outflow of aqueous humor. The RGCs, the innermost cells of the retina, are responsible for sending the transduced light signal to the brain through their axons, which make up the optic nerve (ON). Damage and death of the RGCs with subsequent loss of ON fibers is triggered by a number of insults, most commonly, elevated IOP.
To date, six delivery systems have been tested for ability to deliver genes to the relevant tissues or cells. These are summarized in
Table 1 and include adenoviruses (Ads), adenoassociated viruses (AAVs), herpes simplex viruses (HSVs), lentiviruses (LVs; feline immunodeficiency virus [FIV] and human immunodeficiency virus [HIV]), liposomes (LPs), and naked DNA.