One treatment for neovascular or wet age-related macular degeneration neutralizes the protein linked to the disease using repeated eye injections, an uncomfortable, onerous regimen that causes much anxiety for patients. Gene therapy - if proven to be safe and effective - offers an attractive alternative because one injection could provide lasting effects. Now, a small clinical trial shows that one experimental gene therapy for this significant cause of vision loss in older people appears to be safe and well tolerated.

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Researchers say gene therapy could offer a safe and effective treatment alternative for wet AMD.

A paper on the trial, which was led by Johns Hopkins University School of Medicine in Baltimore, MD, and funded by Sanofi Genzyme of Framingham, MA, is published in The Lancet.

Senior author Peter Campochiaro, a professor of ophthalmology at Johns Hopkins, says: "Even at the highest dose, the treatment was quite safe. We found there were almost no adverse reactions in our patients."

Age-related macular degeneration (AMD) is the third most common global cause of visual deficiency in industrialized countries.

In the United States, National Eye Institute estimates suggest that the number of people affected by AMD will rise to 5.44 million by 2050 - more than double the 2.07 million figure for 2010.

People with AMD lose the ability to see objects clearly and find it increasingly difficult to do everyday things, such as read, drive, recognize faces, and use a computer. As the disease progresses, it destroys the macula, the central part of the retina at the back of the eye that provides sharp, central vision.

The study concerns a type of AMD known as neovascular or wet AMD, which arises when abnormal blood vessels grow beneath the retina. These new blood vessels - neovascular means "new vessels" - can leak fluids that cause swelling and damage to the macula.

Although wet AMD is less common among cases of AMD, it accounts for a high proportion of cases of severe vision loss in AMD.

Need for a less distressing anti-VEGF treatment for AMD

In their study paper, the authors explain that wet AMD is linked to high levels of vascular endothelial growth factor (VEGF), a protein that promotes growth and leakiness of blood vessels.

Treatments that successfully treat wet AMD include injections into the eye of anti-VEGF compounds. However, these need to be given regularly, because after a month or so, the compounds leave the eye and the VEGF levels start rising again.

Eye specialists suggest that the distress and discomfort of such an onerous regimen - often involving repeat injections every 6 to 8 weeks - is likely a main reason patients do not come for injections as often as they should, and their vision gets worse.

Gene therapy is an experimental approach that treats disease by inserting, deleting, or altering genes in the patient. The aim is for doctors to be able use it to treat diseases by "correcting" the underlying genetic causes instead of using drugs or surgery.

Although gene therapy is showing promise in the treatment of some diseases, it is still a risky method and needs to be approached with great caution, which is why at present it is only being tested as a treatment for diseases that currently have no cure.

In this phase I clinical trial, the researchers tested the safety and tolerance of a gene therapy that inserts a gene into retinal cells that causes them to produce sFLT01 - a protein that binds to VEGF and stops it promoting growth and leakage of abnormal blood vessels.

The hope is that, once proven, one treatment of the gene therapy will be enough to cause the cells to become permanent producers of the anti-VEGF protein.

Dramatic results with no serious adverse effects

The vehicle or "vector" the researchers used to deliver the gene is a disabled version of the AAV2 virus that causes the common cold. Viruses are ideal vectors for gene therapy because by their nature they insert genetic material into host cells.

The team enrolled 19 men and women aged 50 and older who had been diagnosed with wet AMD, and assigned them to five groups who received the following doses of viral particles (vector genomes, or vg) in 0.05 milliliters of fluid: 2X10^8 vg (group 1), 2X10^9 vg (group 2), 6X10^9 vg (group 3) and 2X10^10 vg (groups 4 and 5).

The patients were not all treated at the same time. The researchers waited for at least 4 weeks and examined each group to see if there were any adverse reactions before treating the next highest dose group.

The highest dose was not given until the researchers had established there was no dose-limiting toxicity in the first three groups. They found no serious adverse effects in the final two maximum dose groups.

The experimental nature of the trial meant it could only treat patients who were unlikely to regain vision following standard treatment. Because of this, it meant that only 11 of the 19 were likely to show fluid reduction.

The results show that four of these 11 patients experienced dramatic reduction in fluid levels. The levels dropped from severe to almost zero, which Prof. Campochiaro says is what might be expected from standard treatment. Two others from the 11 showed some reduction in fluid in the eyes.

AAV2 antibodies may limit effectiveness

However, the other five patients from the 11 that might be expected to benefit from the therapy showed no reductions in the fluid in their eyes.

Further tests showed that these patients all had antibodies to the strain of AAV2 virus used in the gene therapy. The researchers suggest that the antibodies may have destroyed the virus particles carrying the therapeutic gene before they could insert it into the retinal cells.

However, due to the small number of patients in the trial, they cannot be sure if this is really the cause or just a coincidence.

Should further studies show that the presence of AAV2 antibodies in patients renders the treatment ineffective, then it could mean that as it stands, the gene therapy may have limited use in the U.S., where around 60 percent of people are likely to have antibodies to the family of viruses that AAV2 belongs to.

However, the trial achieved its main purpose in showing that this particular gene therapy, regardless of effectiveness, is safe and well tolerated, and it moves the search for a new treatment for wet AMD forward. Prof. Campochiaro concludes:

"This preliminary study is a small but promising step towards a new approach that will not only reduce doctor visits and the anxiety and discomfort associated with repeated injections in the eye, but may improve long-term outcomes because prolonged suppression of VEGF is needed to preserve vision, and that is difficult to achieve with repeated injections because life often gets in the way."

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