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By Roibeard O’hÉineacháin

GOTHENBURG — Retinal transplantation for the treatment of disorders like retinitis pigmentosa is looking more promising than ever and human trials with such techniques are likely to begin soon, a Swedish researcher told the 7th International Conference on Low Vision.
Retinal transplantation represents a formidable challenge to medical science, but recent advances in vitreoretinal surgery and an improved understanding of cellular physiology have brought researchers several steps closer to the successful use of this approach, Berndt Ehinger MD PhD said.

Early experiments involved the implantation of bits of foetal tissue directly into the subretinal space using a thin capillary tube. These experiments demonstrated that foetal tissues could be transplanted and would differentiate well and survive.
However, the transplants had a disorganised morphology and were poorly integrated, which accounted for the subsequent failure of the technique in human trials in India and the US, he said.
Dr Ehinger noted that what was needed to overcome these problems was a more clinical approach, as he learned when his associate Frederick Ghosh MD, a skilled vitreoretinal surgeon, joined his laboratory.

Dr Ghosh suggested that better results would be obtained by using surgical techniques which were more similar to vitreoretinal surgery in humans.
Dr Ghosh proved his point in an experiment (Investigative Ophthalmology & Visual Science, 1999;Vol 40:133-142) during which he implanted entire embryonic retinas into rabbits.
The implants were placed under the host retina, using a vitrectomy technique. After three and 10 months, electron microscopy showed that while the host retina had degenerated in those places where it was above the transplant, the transplanted tissue had integrated so well as to almost reconstruct the normal retinal appearance.

“The transplant survived for about a year with very good morphological integration between transplant and host. Even a trained histologist would have difficulty seeing where the boundary was between the transplant and the host,” Dr Ehinger noted.
Furthermore, subsequent experiments have shown that retinas transplanted in this way actually transmit visual information to the brain. For example, in a study carried out by Gustaw Woch and associates at University of Louisville, Kentucky (Investigative Ophthalmology and Visual Science 2001;42:1669-1676) rats with such implants had visually evoked responses in an area of the optic lobe corresponding to the portion of the retina in which the transplant was placed.

The next step towards retinal transplants in humans involved the transplantation of pig retinas. Porcine retinas are more similar to human retinas than rat retinas in size and more similar to human eyes than rabbit retinas in vascularisation.
Dr Ghosh has already succeeded in transplanting sheets of retinal tissue into the eyes of transgenic pigs genetically engineered to carry a rhodopsin mutation, which causes the photoreceptors to degenerate in humans.

“Six months after the transplant, the entire retina looks normal. We would have expected photoreceptors to be gone in the areas outside of the transplant but it appears that transplantation has some sort of survival effect promoting survival of native mutant cells,” Dr Ehinger said.
Other types of retinal transplants which are on the horizon include the transplantation of stem cells and retinal pigment epithelium cells.

These have the advantage of not requiring whole retinas for implantation. Such tissue is likely to be scarce for the foreseeable future. But both approaches also have inherent disadvantages
Dr Ehinger noted that at his own centre, Karin Warfvinge MD and Anita Blixt MD found that when they injected stem cells into the subretinal space, the cells spread over the entire retina. However they did not differentiate into neuron progenitor cells as hoped.
“Generating stem cells is quite easy these days. Making them differentiate in the desired way is another matter.
“We wanted these cells to become photoreceptor cells and they steadfastly refused.

We don’t know why but we hope to find out. In the meantime we are hopeful that we can induce these cells to become sources as growth factors,” Dr Ehinger said.
The implantation of retinal pigment epithelium cells has already been tried in humans but without much success. Such transplants have an inherent technical difficulty in that the retinal pigment epithelium is actually what provides the barrier between the retina and the epithelium. The transplants may therefore undermine the immune privilege of the retina.

Dr Ehinger noted that experiments to date have established that retinal transplantation is feasible and that they can preserve and restore vision in eyes affected by tapeto-retinal degenerative disorders.

He also said he expects human trials to begin soon. For the present, it is up to the ophthalmologists to help identify patients who might benefit from such procedures.
“The first attempts failed because of immature technique. Techniques have since improved. I think it is reasonable now to go to human trials on a small scale.
“In the initial stages we will look at procedure safety and biological safety and attempt to untangle any ethical problems. There will certainly be failures and we will have to select patients carefully,” he added.

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