Editors' ChoiceGene Therapy

Boosting the success of retinal gene therapy

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Science Translational Medicine  30 Sep 2015:
Vol. 7, Issue 307, pp. 307ec170
DOI: 10.1126/scitranslmed.aad3065

Inherited diseases of retinal degeneration such as retinitis pigmentosa (RP) are characterized by progressive loss of photoreceptor cells in the retina. These hereditary disorders are potentially treatable with gene therapy; however, in the clinic, gene replacement through viral vector delivery of the therapeutic gene has only provided transient amelioration of retinal degeneration. Why is this? There are two possible explanations: (i) the therapeutic intervention came too late to have a complete therapeutic effect or (ii) the viral vector did not deliver sufficient therapeutic gene to cells carrying the mutant gene. In a new study, Koch and co-workers set out to resolve this conundrum.

The authors developed a mouse model of human RP in which the mouse photoreceptor cells carried one mutant copy of the Pde6b gene and a second healthy allele engineered to be activated by Cre recombinase. The Cre recombinase itself was activated in the photoreceptor cells by systemic administration of the drug tamoxifen. The authors induced expression of the healthy allele during early, middle, and late stages of retinal degeneration and were able to halt photoreceptor cell loss at all stages. The authors concluded that expression of the therapeutic gene even in later stages of disease could prevent photoreceptor cell death and halt retinal degeneration as long as sufficient quantities of the healthy gene were present. Although it remains unclear whether these findings are applicable to all diseases of retinal degeneration, this study suggests that more efficient delivery of the therapeutic gene to affected cells will be the key to success for gene replacement therapy.

S. F. Koch et al., Halting progressive neurodegeneration in advanced retinitis pigmentosa. J. Clin. Invest. 10.1172/JCI82462 (2015). [Full Text]

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