GENE THERAPY FOR DAMAGED CORNEAS

Gene therapy may provide ways to repair damaged corneas and improve the quality of donor corneas, according to Francois Malecaze MD, CHU Toulouse, Toulouse, France. “The possible benefits of gene therapy for corneal disease include a reduced need to administer topical treatments, and gene therapy could better target the molecular mechanisms involved in disease making it more effective and more specific,†Dr Malecaze told the XXIX Congress of the ESCRS.

He noted that the technology of gene therapy has been advancing rapidly in recent years and already clinical studies are under way employing gene therapy in the treatment of retinitis pigmentosa. Research is not as far advanced in the gene therapy of corneal disease, but it is catching up, with numerous strategies under development, he added.

Current research in gene therapy for the cornea is targeting three types of the cells. They are the epithelial cells, for the restoration of corneal surface integrity, the keratocytes of the stroma, to treat corneal opacities, and the endothelial cells to better preserve the endothelium in corneas donated for keratoplasty procedures.

In studies where gene therapy has targeted the epithelium, transfection of genes to epithelial tissue in vitro has been very successful. However, using the same approach in vivo has produced only a very short-lived effect lasting only a day or two.

On the other hand, other research has shown that targeting epithelial stem cells can provide a longer-lasting expression of transfected genes. In studies using different animal models, researchers have been able to excise a small amount of limbal stem cells, transfect the cells in a culture medium with the therapeutic gene and then re-implant the cells in the cornea. The result has been that the progeny of the transfected stem cells migrate to the centre of the cornea (Bradshaw et al, Invest. Ophthalmol. Vis. Sci. January 1999; 40: 230-235).

As regards the keratocytes, Dr Malecaze and his associates have developed a technique for delivering gene therapy to the stroma. It involves injecting a recombinant adeno-associated virus-based vector with a micro-needle. In a study published last year, using this technique to inject the vector with the MMP14 gene in rabbits’ eyes caused corneal scars to fade and corneal transparency to improve as a result (Galiacy et al, Gene Therapy 2011;18:, 462-468).

Another research team has shown that the gene for the fibrosis inhibiting protein, decorin, can be successfully transferred to stromal keratocytes by applying it topically with an adenovirus (after performing a surface ablation with an excimer laser) again reducing corneal opacity (Mohan et al, Invest. Ophthalmol Vis Sci. 2011; 52: 4833-4841).

Gene therapy for the endothelium is at present primarily aimed at improving the quality of donor corneas. The ex vivo approach seems feasible and helps eliminate some of the safety issues involved with in vivo gene transfer.

In a recently published study, human corneas treated with the anti-apoptotic gene p35 had a lower rate of endothelial cell death and remained viable for 11 weeks. By comparison, untreated corneas only remained viable for seven weeks (Fuchsluger et al, Gene Ther 2011 Aug; 18(8):778-87).

“Thanks to the significant advances in molecular biology, retinal gene therapy has started and significant progress has also been made toward taking the next step to allow for gene therapy of the cornea,†Dr Malecaze concluded.