The Why Files The Why Files --

Gene Therapy: The eyes have it!


Genetic blindness: A solution in sight?
Last week, two groups of researchers reported on gene therapy for one type of Leber's Congenital Amaurosis (LCA), a mutation that inevitably destroys vision. The patients in both tests carried a mutation that blocks the production of rhodopsin, which is necessary to convert light into a nerve signal. This particular mutation, called RPE65, affects about 6 percent of LCA patients, or about 3,000 Americans.

Although some young LCA patients may have limited vision, the disease inexorably kills retinal cells, and these people are totally blind by age 40 at the latest. The discovery that certain dogs carry the RPE65 mutation set the stage for a test of a gene therapy. In 2000, a group from the University of Pennsylvania injected a single dose of a virus carrying the RPE65 gene, restoring eyesight for the blind dogs.

Shadowy pink disk shows blood vessels, needle in poised above it.

The needle approaches the retina just before the gene-bearing virus is injected. Image courtesy Jean Bennett, University of Pennsylvania

With no additional treatment, that first dog still sees, says Jean Bennett, a professor of ophthalmology at Penn's Scheie Eye Institute, who also is working on one of the ongoing human tests being conducted at Children's Hospital of Philadelphia.

Results are in. Right?
Viruses are critical to gene therapy because they can ferry genes inside cells. Both of the recent vision studies spliced a working gene to an adeno-associated virus, which does not cause disease. Although adeno-associated virus can enter the cell nucleus, it does not join the patient's DNA, and so should not cause cancer. The virus is also disabled to prevent reproduction -- another key concern.

In both studies, the treatment seemed safe: No virus apparently escaped the eye, there was no inflammation and although there was one retinal tear, there were no showstoppers.

The benefits, however, were uneven. The study by James Bainbridge, at the Institute of Ophthalmology at University College London (see #1 in the bibliography), saw no improvements in objective vision tests. Although one patient could walk much faster through a maze, this is not a valid test of vision (see #2 in the bibliography).

The second experiment, performed at Penn, had better results -- although these small studies are intended to prove safety, not to prove effectiveness. All three patients, ages 19 to 26, improved in objective tests, which, Bennett says, are more reliable than subjective tests, in which the patient may be subject to the placebo effect. One objective test relies on the normal contraction of the pupil that occurs when the retina detects light. If the pupil contracts in dimmer light, vision has improved; that is what happened in Bennett's patients -- but only in the eyes that received the RPE65 gene. (For safety reasons, the gene was injected only in the eye with worse vision.)

Bennett adds that patients were able to read more lines on a vision chart, and they reported subjective improvements. "They all were able to enjoy improved navigation [ability to walk around] and vision in dim light. They began to see things in the bedroom, a crack of light under the door or tiny lights on equipment" (see #3 in the bibliography).

A note of caution
However, neither of the two studies (nor a third that is now under way) can prove that the treatment works, as the National Eye Institute cautioned: "No conclusions can be made at present as to whether gene transfer will restore visual function in people with LCA or impede further progression of the disease. Additional important insights will be gained when investigators have the opportunity to examine the totality of the published data ..."

LCA retina is pale, has few blood vessels, and more brown areas.

At left, the pale, thin, unhealthy retina of an LCA patient. (Compare color and blood vessels to normal eye on right.) When retinal cells die in LCA, vision is permanently destroyed. Image courtesy Jean Bennett, University of Pennsylvania

Still, it's hard to be too hard-nosed in the face of any advance toward treating an untreatable disease. "It's exhilarating, so exciting," says Bennett. "These individuals haven't recovered the sort of vision I enjoy, but they are so grateful for being able to be a little more independent, able to navigate better, to see their loved ones better."

Waxing optimistic after so many disappointments in gene therapy, Bennett adds, "This opens up a lot of opportunity; it's just a beginning. It offers proof that this approach is viable and is safe, at least so far."

Although no gene therapy has yet been approved in the United States, China has approved Gendicine, a treatment carrying a replacement P53 gene, which is a critical natural defense against cancer. In one trial, 64 percent of squamous cell cancer patients who received Gendicine, plus radiation, had a complete regression of the cancer, compared to 19 percent who received radiation alone. However, the evidence on Gendicine is murky, according to a comment in the journal Science (see #4 in the bibliography), which noted that a key published summary by Gendicine's manufacturer (see #5 in the bibliography) obscured or omitted relevant details.

What else is happening in gene therapy?

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Megan Anderson, project assistant; Terry Devitt, editor; S.V. Medaris, designer/illustrator; David Tenenbaum, feature writer; Amy Toburen, content development executive

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