What form of cell death do the photoreceptors of people suffering from retinitis pigmentosa undergo and how can their degeneration be prevented or delayed with pharmaceutical substances? Dr. Paquet-Durand from the Institute for Ophthalmic Research in Tübingen is working to resolve these questions.
One interesting discovery resulting from Dr. François Paquet-Durand’s research is that there are different forms of cell death. The biochemist has been investigating cell death mechanisms associated with photoreceptor neurodegeneration in retinitis pigmentosa for around four years now. Retinitis pigmentosa is a genetic eye condition that leads to blindness. The disorder is characterised by the progressive peripheral loss of photoreceptor cells (i.e. the rods concentrated at the outer edges of the retina which make night vision possible) that can lead to a loss of central vision. Although the cones that are responsible for colour vision do not usually have a genetic defect, they eventually also degenerate as the disease progresses. Retinitis pigmentosa symptoms progress from night blindness to the reduction of the peripheral visual field (tunnel vision) leading eventually to complete blindness. The development of effective medical treatments requires the investigation and clarification of the cell death mechanisms of the photoreceptor cells.
Around 45 rod-related genes are known which, when mutated, can lead to retinitis pigmentosa. However, Paquet-Durand’s investigations found that most of the biochemical processes involved in photoreceptor degeneration are not associated with established cell death mechanisms such as apoptosis or necrosis. “We found that some processes are associated with apoptosis, i.e. programmed cell death, and some with necrosis. However, we also found processes that are not associated with either of these two forms of cell death.” Although there is little evidence that substantiates the presence of apoptotic mechanisms, the degeneration of the rods was initially thought to be an apoptotic process because some parts of the process were identical.
In the classical process of apoptosis, mitochondrial cytochrome C is released into the cytosol where it induces the formation of apoptosomes, protein complexes that boost the death of cells. Proteolytic enzymes, i.e. caspases, play a key role in apoptosis where they are overexpressed and activated. “We found no evidence that this is the case in photoreceptor cells. We did not find any cytochrome C in the cytosol nor did we find any up-regulated and activated caspases. In addition, apoptosis inhibitors had no effect. Although all this has been known for around 15 years, little attention has been given to these findings, explained the researcher.
Paquet-Durand mainly uses tissue slices and cultures of explanted retinas that can be kept in the laboratory for up to six weeks. “The advantage of this procedure is that we can monitor changes under controlled conditions,” said Paquet-Durand. Since at the moment there are hardly any markers for degenerating photoreceptor cells available, reliably identifying these cells is a huge challenge. Amongst other things, his team is looking for characteristic morphological changes such as signs of cell nucleus decondensation. Besides these investigations, the group of researchers is also aiming to develop markers to work on in the future, which would also benefit the search for effective drugs.
But Paquet-Durand does not want to raise unrealistic hopes, as he is aware that the processes that need to be targeted are highly complex. “Realistically, I believe that due to the genetic heterogeneity of retinitis pigmentosa, it will not be possible to fully cure the disease in the near future. I do not believe that it is possible to completely prevent the degeneration of the photoreceptors in the near future, but I do believe that we will be able to slow down the progression of the disease.”
Enabling medical treatment would be an important piece in the jigsaw puzzle in terms of the effort to save, or even restore, the vision of retinitis pigmentosa sufferers as much as possible. Such medical treatment would be used in combination with other therapeutic approaches. A completely different approach is the electronic retinal implant that was also developed at the Institute for Ophthalmic Research at the University of Tübingen by researchers led by Prof. Dr. Eberhart Zrenner. The implant has already been used to treat 18 blind people. The retinal implant replaces degenerated photoreceptors with technical light sensors. However, such an implant can only be used for the treatment of patients who are completely blind and, as such, cannot be treated with drugs. “Our approaches are very different, but could complement each other. I believe that in about ten to twenty years’ time we will be capable of delaying the degeneration of photoreceptors for a period of time that would allow us to further develop the retinal implant,” said Paquet-Durand.Over the next few years, Paquet-Durand and his team will focus on increasing their knowledge of the specific cell death of photoreceptors and in particular investigating the role of the epigenetic process in the degeneration of photoreceptors. He also hopes to be able to find out why retinitis pigmentosa also leads to the degeneration of the cone photoreceptors, although the genetic mutations that have been discovered only affect the rods. The secondary degeneration of the cones is not yet understood in detail and further research is necessary to obtain further insights into the process. “One reason might be related to changes in oxygen supply. But we do not know for sure and want to focus on this in greater detail. In animal experiments, we have already found that cones with mutations undergo similar cell death processes to rods,” said Paquet-Durand.