December 3, 2003.
By Roger Highfield,
The quest to help the blind to see is no longer the province of miracles. Surgeons and scientists are increasingly confident that restoring lost vision is feasible, at least for some. And much of this growing confidence rests on their burgeoning knowledge of why nature makes such a mess of repairing eyes.
The understanding could benefit more than those affected by eye injury and disease. Having difficulty with focusing affects many people above the age of 40, and scientists are coming closer to the day when an old lens, stiffened by age, could be replaced with a soft, artificial one to restore youthful vision.
Second sight: turning off the body's repair mechanism could reuduce the side effects of cataract surgery
Surgeons are wary of eye operations for the same reason that blindness and impaired vision are so common: scar tissue is a common side effect of injury, disease and operations. And scar tissue can wreck the workings of the eye.
Evolution has seen a trade-off between the need to regenerate and the need to repair damage. Making good a wound with rapidly-growing scar tissue, principally to stop infection, does not mean the same thing as making good a damaged eye. Better to put up with disorganised scar tissue to halt the risk of infection, even if it does put an eye out of operation, than leave an open wound so as to facilitate eye regeneration.
"Somewhere in evolution, we have lost our ability to regenerate," says Peng Tee Khaw, professor of ocular healing and glaucoma and head of the ocular repair and regeneration biology group at Moorfields Eye Hospital and the Institute of Ophthalmology. "Our genes don't normally regenerate the eye, they just repair it."
For reasons not fully understood, not all living things have made this "choice" in evolution. The salamander wallows in unhygienic conditions yet is able to replace its spinal cord, gills, parts of the brain, jaw and parts of the heart, along with its limbs and tail. And, to the envy of eye surgeons, its retina and iris, too.
But the problem remains that humans lack the regenerative abilities of the salamander and possess eye-repair mechanisms that often cause blindness. Prof Khaw is one of a team at Moorfields and the institute trying to sidestep this by turning off natural repair mechanisms and enhancing natural regeneration.
The new International Children's Eye Centre planned for the Moorfields site will build on this understanding for improving the treatment of young people with eye problems, a venture readers can support by backing the Daily Telegraph's Christmas charity appeal (see link).
Repair mechanisms culminate in scarring, probably the major culprit when it comes to loss of sight. To find out what triggers scarring, when a disorganised mixture of proteins and cells patch up an injury, Prof Khaw and colleagues studied molecules that circulate in the eye.
About a decade ago they found that one protein, called transforming growth factor (TGF) beta, seemed particularly important. It is no accident that previous work in Manchester revealed how this protein is almost absent from the foetus, which does not scar. This offered new hope of a way to prevent scarring by blocking TGF beta.
Prof Khaw had shown that a quick and easy way to prevent scarring was to use a sponge to apply a drug that is also an anti-cancer agent. Although now the most commonly used method in the UK, it can have some side effects.
To devise a more subtle way to achieve the same end, Prof Khaw's group teamed up with a company called Cambridge Antibody Technology, a specialist in devising molecules, called antibodies, that can bind to, and knock out, other molecules. In this case, the target was TGF beta.
The team decided to test the antibody in the treatment of glaucoma, a leading cause of blindness, where the reduction of the normal flow of fluid through the drainage channels in the eye causes the build-up of pressure and damage to the eye.
There is an operation, called a trabeculectomy, to make a little trapdoor valve in the eye. However, subsequent scarring can cause problems, particularly for children: they heal more quickly but suffer more scarring as a result. "This remains a serious problem," says Prof Khaw. "When the operations fail, the children can then go blind from glaucoma.''
Now surgeons are injecting the antibody Trabio (lerdelimumab) into the skin around the eye to prevent scarring during trabeculectomies. A pilot trial showed that the tissue looked much more natural and that there was little scarring after the operation. "That was very exciting for us. That was the first time a protein antibody against TGF beta was used in patients," he says.
Doctors are now half way through several larger international studies. One hope is that the antibodies will mop up TGF beta without significant side effects. "So far, the results have been promising," says Prof Khaw, who hopes the antibody can be used to make glaucoma operations last for life.
The antibodies could find other uses. One common cause of blindness, particularly among the elderly, is macular degeneration. In one form of the disease, blood vessels leak under the retina. As a consequence, there is also secondary scarring. Although many new therapies for macular degeneration are under development to halt blood vessel growth, "anti-scarring therapy could help," says Prof Khaw.
TGF beta is also important in the tissue repair that leads to damage to the optic nerve at the back of the eye caused by glaucoma. "If we can stop the optic nerve being compressed in glaucoma we can prevent people ever becoming blind," says Dr Francesca Cordeiro, head of the glaucoma and optic nerve research group. She is developing new methods of halting the scarring processes in the retina in glaucoma with novel gene therapy and drugs to stop nerve cells from dying.
Teams at Moorfields and the Institute of Ophthalmology are also studying repair mechanisms at work in the lens of the eye. This, they hope, will improve the success of a very common operation to replace a lens that has become clouded by dead cells (cataracts).
Unfortunately, up to 30 per cent of patients who undergo cataract surgery suffer a secondary loss of vision over time that necessitates corrective surgery. The problem lies with a "bag" in the eye that contains the old cloudy lens which has to be replaced.
During the cataract operations, the old lens is sucked out of the bag and replaced by a plastic lens. But this can trigger repair mechanisms in the bag, causing it to contract and turn stiff and opaque, "like a plastic bag in the sun", says Prof Khaw. As well as ruining the operation, the same repair mechanism prevents much more flexible artificial lenses from being implanted because they would be constrained by "a bag of scar tissue".
One approach would be to use the antibody or other anti-scarring treatments to turn off this repair mechanism. As well as preventing a common side effect of millions of operations, it would also realise a long-held dream of ophthalmologists: they would be able to insert into this flexible capsule an accommodating lens, perhaps by injecting materials such as hydrogels, which are elastic just like the natural lens.
"The reason you can read a newspaper is that your lens is accommodating, getting fatter and smaller: it is not stiff. If the capsule can be prevented from going stiff, then flexible lenses under development around the world could allow you to read without reading glasses," says Stephen Tuft, a cataract and cornea specialist at Moorfields.
Other research is concentrating on how to regenerate tissue. One approach is to make vital cells multiply again. The Moorfields consultant Frank Larkin is studying innovative ways, including gene therapy, to make the non-repairing endothelial cells which line the inside of the clear corneal window divide again and repair the eye. These cells pump water out of the eye; when they fail the cornea goes cloudy. Restoring these cells could clear the cornea, meaning a corneal transplant with the risks of rejection would not be required.
Another approach is to use "parent" cells, or stem cells, from which all other types grow. These parent cells are exploited by the salamander: when they sever a limb, stem cells form a mound called a "blastema" and re-differentiate to form the tissue to rebuild the limb.
Injuries to the cornea and certain diseases cause failure of the stem cells found on the outside of the cornea, and this failure is responsible for the blindness that strikes with a disease called aniridia. As a consequence, abnormal tissue invades the cornea and makes it opaque. "If we could replenish these stem cells, we could not only help this condition but also treat other diseases or eye damage," says Dr Julie Daniels, head of the epithelial stem-cell transplant laboratory.
For this kind of use, and for cells to repair the back of the eye (retina) too, a "state of the art" stem-cell transplant unit is being built at the institute and Moorfields. Transplant of stem cells or regenerated cells from a donated eye - or even from a patient's healthy eye - could help restore sight in children and adults.
"Scarring or poor regeneration of tissue plays a role in every major blinding disease in the world today, in both children and adults," says Prof Khaw. "If we could fully understand and control these processes, most of the children with glaucoma that I see could be cured for life, and better still, we could begin to prevent or treat most of the blinding diseases that are currently untreatable.''
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