cGMP as a key player and therapeutic target in Retinitis Pigmentosa

Inherited retinal degeneration relates to a group of diseases affecting the rod and cone photoreceptors of the retina. The diseases include Retinitis pigmentosa (RP), which is considered as a rare disease, with a prevalence of about 1:3.000 - 1:4000. At the same time RP has a high genetic diversity, with disease causing mutations in over 60 specific genes known (see sph.uth.tmc.edu/retnet).

The RP disease regretfully often starts at a young age, usually with rod degeneration followed by a secondary death of cones - the cells far more critical for human vision - and thus often leading to complete blindness. Due to the genetic diversity the RP variants are clinically heterogeneous, but they all: a) cause photoreceptor death and vision loss, b) have unexplained mechanisms, and c) lack established treatment.

We argue that a viable therapeutic strategy would be to target a disease driving molecular process common to several RP types, in order to develop a neuroprotective approach to be used on, if not all, then at least many types of RP, irrespective of the exact mutation. Thus, to define a common disease pathway or component on which different RP variants converge would be most valuable.

In our studies on the RP mechanisms and on potential therapies, we use animal models with mutations homologous to those seen in RP patients. In doing so, we have observed increased levels of photoreceptor cyclic guanosine-monophosphate (cGMP) in several genetic variants of the disease, representing a substantial percentage of the RP types. Moreover, the high cGMP appears to be detrimental to the photoreceptors, probably via crucial cGMP interactors, and high cGMP is also a very early event in the degenerative processes of individual photoreceptor cells. Together this suggests that the cGMP system (cGMP and its interactors) represents an ideal molecular target for a mutation independent therapy.

This thinking was used in the EU 7th framework project DRUGSFORD, which investigated the therapeutic potential of cGMP analogues, able to target cGMP signalling with very high specificity and efficacy, and how a liposome based drug delivery system (DDS) promoting transport across the blood-retina-barrier would help in this respect. DRUGSFORD (www.DRUGSFORD.eu) encompassed both academia partners (with PE as ULUND partner) and small-to-medium enterprises, and the aim was to produce a compound and DDS combination, test it at various levels (cells, tissues [explants], and in vivo), and make it ready for clinical evaluation after end of project.

Based on very successful in-project-results DRUGSFORD now has a DDS packaged cGMP analogue for RP treatment as a drug candidate. In March 2015 the active substance received Orphan Drug Designation (ODD) by the European Medicines Agency (EMA) (EU/3/15/1462), and there are currently several initiatives ongoing to try to move the candidate towards clinical trials, including by forming a company to attract investors.

At the same time the studies on the RP mechanisms continue, since the way the cGMP system affects cell death and survival in RP photoreceptors is not known in necessary detail. This is important to address, not the least since a deeper mechanistic knowledge will be helpful for any treatment principle. A current question is: Which are the cGMP interaction partners in the photoreceptors? While prototypic cGMP interaction partners include cGMP-gated ion channels (a.k.a. cyclic nucleotide-gated channels, CNGs) and cGMP-dependent protein kinase (PKG), it is likely that also other cGMP interactors exist. An understanding of this will have a direct bearing on how to best interfere with the pathological events.

Another question concerns if the affected photoreceptors can release their cGMP, so as to relieve themselves of this biochemical burden. Using organotypic retinal explant cultures we have recently noted that degenerating retinas release high amounts of cGMP into the medium in comparison to healthy control retinas. This appears to be a novel aspect of the disease, and could give rise to new insights into the molecular pathology of RP. Importantly, cGMP released by the photoreceptors may find its way into the blood stream, where it could act as a disease correlate or marker. Encouragingly, in a collaboration with Sten Andréasson and Ulrika Kjellström at the Eye Clinic in Lund, we have very recently reported that patients with a mutation in a gene for PDE6A, a component related to the cGMP system, have clearly higher levels of cGMP in their blood (plasma).

The laboratory therefore continues its quest for more knowledge on the cGMP system in the context of inherited photoreceptor degeneration.