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E. A. Klausner, R. L. Chapman, S. V. Andurkar; Pharmaceutical Aspects of Corneal Gene Therapy. Invest. Ophthalmol. Vis. Sci. 2008;49(13):4296. doi: https://doi.org/.
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To study the pharmaceutical aspects of corneal gene therapy (CGT). Along with tissue engineering, gene therapy approaches stand at the forefront of advanced biomedical research to treat blindness arising from corneal diseases. The single major barrier for effective gene therapy in general and CGT in particular, is the delivery.
A literature search using PubMed (1994-2007).
Most of the traditional DNA vectors of gene therapy have been tested in CGT, including viral vectors such as adenovirus, adeno-associated virus, lentiviruses and retroviruses, and the non-viral vectors of naked DNA, cationic lipoplexes and polyethylenimine. Recently the use of small interfering RNA duplexes and a plasmid DNA encoding short hairpin RNA in the cornea were reported. Generally, viral vectors find substantially more common use in gene therapy than non-viral vectors; however, CGT studies do not follow that pattern, as viral vectors were used in approximately 47% of the studies.Consistent with previous findings, it was demonstrated in CGT that viral vectors are generally more efficient than the non-viral vectors, and in comparison to naked DNA, administration of polyplexes offers the potential advantages of enhancing the transgene expression and the biological effect.The choice of the delivery system in CGT has utmost importance since in the eye even a mild inflammatory response might impair vision. A few CGT studies showed mild to severe inflammation following intracameral injection of adenovirus. In one such study, the inflammatory response that appeared in histologic examination demonstrated no gross external manifestations thereby highlighting the importance of awareness of potential side effects and cytotoxicity in the design and evaluation of corneal gene delivery systems.Due to the advantages of local delivery, the majority of corneal gene delivery studies used ocular (e.g., intracameral, intravitreal and intracorneal injections), as opposed to peripheral, modes of administration. The challenge of achieving effective topical gene transfer, presumably due to tear flow, blinking and low penetration of the vector through epithelial tight junctions left no alternative but invasive local administration. The ocular mode of administration was correlated with the intracorneal location of gene expression since the site of microinjection controls the type of cells that receive the transgene.
Pharmaceutical considerations, and in particular the delivery system and mode of administration used, have a substantial impact on the outcomes and applicability of CGT studies.
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