There is much excitement in the news today about reports that doctors at Moorfields Eye Hospital have used gene therapy to dramatically improve the night vision of an 18-year-old man suffering from Leber’s congenital amaurosis. This disorder leads to a progressive loss of vision, and in many patients blindness at an early age. Until now there has been no effective treatment available for the condition.
Defects in several genes can cause Leber’s congenital amaurosis. In this trial which is published in the New England Journal of Medicine (1) the scientists focussed on a gene called RPE65, an enzyme which is crucial to the production of 11-cis retinal that rod photoreceptor cells in the eye need so that they can respond to light. They hoped that injecting an andeoviral vector that produced healthy RPE65 gene into the back of the eye would slow down or even reverse the deterioration in vision. Accompanying this paper in NEJM is another by a group based in Pennsylvania who found that gene therapy with RPE65 improved vision in three patients with Leber’s congenital amaurosis, though the benefits were more modest (2)
This work was underpinned by years of research in animal models of Leber’s congenital amaurosis, which demonstrated that gene therapy could safely treat the disorder (1). While transgenic mice were used in some of this research, several key studies involved the Swiss Briard dog, which is prone to progressive loss of vision due to a naturally occurring defect in the RPE65 gene (3,4). While these first human trials are underway further animal research is continuing to develop new vectors that deliver RPE65 specifically to cells of the retinal pigmented epithelium, the cells where loss of RPE65 causes the most problems, and which may produce better results than the method reported today (5). Interestingly the animal studies indicate that there is a window of opportunity within which therapy must be started for benefits to be seen, and it is probably no coincidence that in the Moorfield’s Eye Hospital trial the patient who responded to the therapy had the least advanced disease of the three trial participants.
The trial results announced today are very encouraging, but it’s important to remember that this is only the beginning. Research, both in animals and humans, will continue to improve gene therapy for Leber’s congenital amaurosis, and in the near future we will no doubt be hearing more about the use of gene therapy to treat other once incurable diseases.
1) Bainbridge J.W.B. et al. “Effect of Gene Therapy on Visual Function in Leber’s Congenital Amaurosis” NEJM Online April 27 2008, http://content.nejm.org/cgi/content/full/NEJMoa0802268, DOI:10.1056/NEJMoa0802268
2) Maguire A.M. et al. “Safety and Efficacy of Gene Transfer for Leber’s Congenital Amaurosis” NEJM Online April 27 2008, http://content.nejm.org/cgi/content/full/NEJMoa0802315, DOI:10.1056/NEJMoa0802315
3) Acland G.M. et al. “Gene therapy restores vision in a canine model of childhood blindness.” Nat. Genet. Vol. 28, Issue 1, Pages 92-95 (2001), DOI:10.1038/88327
4) Jin M. et al. “Rpe65 Is the Retinoid Isomerase in Bovine Retinal Pigment Epithelium” Cell Vol 122, Pages 449-459 (2005), DOI:10.1016/j.cell.2005.06.042
5) Le Meur G “Restoration of vision in RPE65-deficient Briard dogs using an AAV serotype 4 vector that specifically targets the retinal pigmented epithelium” Gene Ther. Volume 14, Issue 4, Pages 292-303 (2007) DOI: 10.1038/sj.gt.3302861
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Following up on the two trials reported above a third clinical trial published this week in the journal Human Gene Therapy (1) has also reported that gene therapy with RPE65 improved vision in three patients with Leber’s congenital amaurosis.
This trial was a phase I trial whose main purpose was to assess the safety of the treatment, but which also measured changes to vision. A major difference between this study and the previous two studies is that the immune system of the patients was not suppressed before the treatment. Previously it had been believed that the immune system might block the treatment, but this study indicates that this is doesn’t happen. You can find out more about the new trial on <>
1) Hausewirth W.W. “Phase I Trial of Leber Congenital Amaurosis due to RPE65 Mutations by Ocular Subretinal Injection of Adeno-Associated Virus Gene Vector: Short-Term Results.” Human Gene Therapy Online September 7 2008. <>
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