Retinitis pigmentosa (RP) is a group of severely disabling inherited neurodegenerative diseases. Typically, rod photoreceptor cells—permitting vision under dim light conditions—degenerate first during the course of the disease. Subsequently, the loss of rods triggers a secondary degeneration of cone photoreceptor cells, the source of high-resolution colour vision in daylight, eventually leading to complete blindness.
Retinitis pigmentosa is caused by a wide and disparate set of mutations, currently identified in over 70 genes (cf. retinal information network: https://sph.uth.edu/retnet). Although many of the causative mutations have been defined, there is still only very little information on the subsequent degeneration mechanisms. The details that we know so far have mostly come from studies on animal models (usually rodent based), that display gene mutations homologous to human retinitis pigmentosa patient cohorts.
The genes mutated in retinitis pigmentosa are usually associated with photoreceptor function, but there are also such that relate to general cellular functions (Kennan et al. 2005, Trends Genet. 21, 103-110). The molecule cGMP (cyclic guanosine-monophosphate) plays a direct role in the phototransduction cascade, which takes place within the photoreceptor cells when these are hit by light. In many cases, retinitis pigmentosa mutations lead to an excessive accumulation of cGMP in photoreceptors (Arango-Gonzalez et al. 2014 PLoS One. 9, e112142), for instance in situations where genes for enzymes involved in photoreceptor cGMP metabolism are affected. This is the case for mutations in phosphodiesterase 6 (whose subunits are encoded by genes PDE6B, PDE6A, PDE6G and PDE6C, PDE6H for cone photoreceptors) the photoreceptor enzymes that hydrolyse cGMP to GMP. The Pde6b gene is mutated in the rd1 mouse model of retinitis pigmentosa, which has been well studied in many laboratories. In a supposed chain of events, the accumulation of cGMP in PDE6B mutant retina occurs as a direct consequence of the actual gene defect, and this may thus be seen as an early and mechanistically fundamental degeneration component. In the next step(s), the increased cGMP can be envisaged to have at least one of four targets: 1) cGMP dependent protein kinase (protein kinase G; PKG), which when activated by cGMP, will phosphorylate specific proteins, 2) cyclic nucleotide gated ion channels (CNGC), which, when activated by cGMP, allow for a cGMP controlled influx of Na+ and Ca2+, 3) phosphodiesterase (PDE), and 4) hyperpolarization-activated cyclic nucleotide-gated (HCN) channel. The first two cGMP targets are directly connected with photoreceptor degeneration (Paquet-Durand et al. 2009, J. Neurochem. 108, 796-810; Paquet-Durand et al. 2011, Hum. Mol. Genet. 20, 941-947), while the others are known cGMP targets and hence potentially involved in the degenerative process. Due to their direct connection with the early events, PKG and CNGC can be regarded as disease drivers, even though the downstream mechanisms are still not understood in great detail (Trifunovic et al. 2012, Curr. Mol. Med. 12, 598-612).
There are a variety of experimental treatment approaches for retinitis pigmentosa that are currently being researched and which are at different stages of development, including e.g. gene therapy, stem cell research and optogenetics. However, currently there is no clinically approved treatment available.
Previously, certain cGMP-derived PKG inhibitors, e.g. Rp-8-Br-cGMPS, were found to offer some protection of rd1 and rd2 photoreceptors both in vitro and in in vivo mouse retinitis pigmentosa models (Paquet-Durand et al., 2009). However, these PKG inhibitors would require frequent re-administration (i.e. every other day) of the PKG inhibitor by subtenonal or intravitreal injection, which is not practical for a chronic disease.
There are currently no approved prevention or treatment methods available for retinitis pigmentosa. There is therefore still a need in the art for adequate treatments of retinitis pigmentosa, in particular treatments with a more convenient mode of administration. It is thus an object of the present invention to provide for new means and methods for treating and preventing retinitis pigmentosa.