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Gene therapy implies the delivery of genes to somatic tissues for therapeutic purposes.12 The eye is an attractive target for gene therapy because of its accessibility and its immune privilege. However, over the past few years gene therapy has taken some hard knocks, both from a disillusioned stock market and, more tellingly, from a distinguished peer review committee.34The latter concluded that more time should be spent on understanding and improving potential strategies at a basic science level and less on publishing hasty, poorly controlled clinical experiments. The premature scramble towards clinical studies prompted the taunt ‘less hype, more biology’ in a Science article.5 The question arises as to whether there are lessons here for the expanding group of researchers working towards ocular gene therapy.
One of the most stringent tests of a gene therapy would be to replace the function of a defective ocular gene, since this requires the introduction and long term expression of a functional copy into many, if not a majority of, target cells. In the case of the retina, for example, specific genetic defects have been found in 20 of the 87 mapped genes causing genetic eye disorder.6 Most of these disorders result from single gene defects which are both highly disabling and potentially correctable. As an alternative, transferred genes expressing growth factors may be therapeutic in some of the degenerative disorders.7 These aspects of gene therapy have therefore attracted a growing body of researchers bent on revolutionising their treatment.8-14
As long term gene expression is the goal, success depends on (i) efficient uptake into the target cells; (ii) avoidance of endocytosis and lysosomal degradation; (iii) import into the nucleus; (iv) stable retention in the nucleus, either as a circular episome (for example, adenovirus) or by integration …