Gene therapy scored another success this week, at least in the preclinical arena, with a report that scientists were able to use gene therapy to improve the structure and electrical function of both photoreceptor cells and the cells they connect to in dogs with the degenerative eye disease X-linked retinitis pigmentosa.

The study, which appeared in the Jan. 23, 2012, advance online edition of the Proceedings of the National Academy of Sciences, marks the first time that scientists have successfully used gene therapy to treat photoreceptors – the cells in the eye that sense light and translate it into neural signaling.

The disease name retinitis pigmentosa, William Beltran told BioWorld Today, is itself "an umbrella term to describe inherited retinal degeneration that affects the photoreceptor cells."

Beltran is an assistant professor of ophthalmology at the University of Pennsylvania's school of Veterinary Medicine, and the first author of the paper reporting his team's results.

The authors tested the ability of their vector, a modified adeno-associated 2/5 virus containing the gene for retinitis pigmentosa GTPase regulator, or RPGR, to affect the course of retinitis pigmentosa. While there are dozens of genes in which mutations can lead to retinitis pigmentosa, mutations in the RPGR gene are the most common cause of X-linked retinitis pigmentosa, and one of the most common causes of retinitis pigmentosa in general.

The authors showed that when dogs were treated with the full-length RPGR gene, both types of photoreceptors – rods, which are important for vision under conditions of low light, and cones, which are for color vision – took up the gene. That led to improved structure of both the photoreceptor cells themselves and the brain cells they connect to, as well as improved electrical activity.

The team's next plans are to conduct longer-term preclinical safety and efficacy studies that include behavioral studies, since one thing that is not yet clear is whether those changes will ultimately allow treated animals to see any better.

"We did not perform, in our study, any visual behavior tests," Beltran acknowledged. That is partly because of the nature of retinitis pigmentosa, which causes people – and the dogs that Beltran and his team treated – to lose their sight "very gradually." The other cause of blindness that has been treated successfully with gene therapy, leads to much more severe vision loss earlier in life, though it does not cause photoreceptor cells to degenerate. (See BioWorld Today, Aug. 13, 2009.)

People with the disease lose their sight over the course of decades; and in the work now published in PNAS, Beltran and his colleagues treated the animals early on enough so that visual improvements would have been hard to demonstrate, simply because they still had enough vision left that even untreated animals would have likely aced vision tests such as obstacle courses.

What the team did show was that in treated animals, "we are structurally preserving the photoreceptor cells."

By measuring the electrical activity of cells in the eye via electroretinograms – a method that Beltran termed "a sort of EKG for the retina" – they also showed that the treatment improved the electrical function not just of photoreceptors, but also of the cells that those receptors connect to, so-called second-order sensory neurons.

Beltran said that the improvements in the functioning of downstream cells made his team optimistic that the structural and electrical improvements will be accompanied by improved vision, and also that such improvement "may be possible even if we target late stages of disease."

Gene therapy for another visual disease, Leber's congenital amaurosis, has already seen clinical success. (See BioWorld Today, Aug. 13, 2009.)

The University of Florida's William Hauswirth, who is one of the co-authors on the current paper, is the leader of the group that has successfully treated patients with Leber's congenital amaurosis with gene therapy – a success that was part of what prompted Science magazine to name gene therapy as one of the top advances of 2009.

Hauswirth is co-founder of Alachua, Fla.-based Applied Genetic Technologies Corp., which aims to use adeno-associated virus-based gene therapy for the treatment of degenerative eye disease and "might, in the future, commercialize some aspects of this work," according to the paper's conflict of interest statement

Beltran said that the success of gene therapy in treating visual diseases is partly because the eye is "a small organ that you can easily get to and inject. . . . You don't have to inject intravenously or deliver to the whole body."

The ease of targeting, in fact, may be part of the reason behind the success reported this week in using stem cells to treat macular degeneration. (See related story, p. 1.)

Beltran said a key factor was also identifying the best viral vector possible, which was done by Hauswirth and his colleagues at the University of Florida.

In general, he said, "success has been possible because there has been collaboration between several investigators who have complementary experience."