UNDERSTANDING & TREATMENT OF RP

Research Into Retinitis Pigmentosa:

It has been clear for a long time that RP is a difficult disease, both to understand and to treat. The last 15 years have seen enormous growth in our understanding of what happens to the retina in RP, yet treatment remains elusive.

The year 2000 saw a continuation of research, and growth in research. One way of measuring that growth is to look at how many conferences are being held, either specialist meetings on RP, or RP sections in the large conferences in Europe and the USA. For example, the ARVO (Association for Research in Vision and Ophthalmology) Meeting held each May in Florida, and the biennial meting of ICER (the International Congress on Eye Research), are now preceded each year by a meeting just on retinal degeneration. Specialist meetings on topics such as gene therapy for RP, and mouse models of RP, continue to grow in number.

The growth in understanding is very real. For those of us who work at the bench, for example, one highlight of 2000 was a report from a US group, identifying the gene causing the degeneration in the RCS (Royal College of Surgeons) rat. The gene is called Mertk, and had eluded identification for years. The pathogenesis of RP in the RCS rate is probably better understood than any other form; now we know the gene. Once that identification was made - there was no previous evidence that Mertk was an RP gene - the search was on to test whether mutations in the same gene cause RP in humans. Within months a report appeared, from a US-European initiative, that the mutations in human Mertk cause a form of RP, with the classical signs of a rod- cone dystrophy.

Work on gene therapy continues. Perhaps the most promising form of gene therapy is the 'ribozyme' technology, being used for autosomal dominant RP (it will work only with autosomal dominant forms). Ribozymes are molecules which can destroy the message which a cell issues to make a protein. In autosomal dominant RP, cells are producing both wrong and right messages for a crucial protein. A ribozyme is engineered to destroy the wrong message, leaving the right message free to act. The technology works; it is being packaged into virus-mediated 'delivery systems' - ways of getting it to the retina. The delivery systems are being engineered to last longer and longer (so far months instead of days), and therapy is being trialled successfully in rats.

As the photoreceptors degenerate, the environment of the retina changes. In particular the oxygen levels in the retina rise. This rise was predicted by my own group, and we have made progress using oxygen and light levels to counteract this rise in retinal oxygen. This prediction was elegantly demonstrated experimentally by Professor Dao-Yi Yu's group at the Lions Eye Institute in Perth, in the RCS rat. In joint work we plan to extend this finding to other RP models, helping to understand the state of the retina in late stages of RP. As always, it is hoped that this understanding will open a way to therapy, to slow the degeneration. Other Australian groups continue work of high international standard, focussed on RP. Dr Kalloniatis' group in Melbourne is demonstrating the metabolic steps in the pathogenesis of the rd degeneration in mic; this form of RP has a human analogue. And Dr Piroska Rakoczy's group in Perth is developing a highly innovative ways to deliver therapeutic agents to the degenerating retina.

The retina also produces protective proteins (trophic factors) to try to stabilise its cells in the face of genetic or environmental stress, and research groups continue to discover the mechanism of this protection and the way in which such factors might be delivered to the eye, to protect the RP retina, and slow the degeneration.

The last criticial stage in retinal degeneration is the death of retinal cells, especially photoreceptors. A great deal of research has been done on the mechanisms of cell death in recent years, often in the context of diseases caused when cells which should die do not (i.e. the cancers). A group in Ireland reported during 2000 success with drugs engineered to interfere with the process of cell death, and keep cells alive, slowed retinal degeneration in a mouse model. The drugs are patented, and the work is, as yet, unpublished, so relatively little is known of how they work. The media reports indicate that clinical trials are planned.

So 2000 was a year of more progress in understanding, and more steps towards therapy, with Australian groups making, with Retina Australia's generous support, important and distinctive contributions. However, effective therapy is still some time away.