DRUGSFORD Scientific summary
Background
Vision is by many regarded as the most precious of our senses, and to see we need to have a functioning retina, with well working photoreceptors. The retinal photoreceptors – rods and cones – are the light capturing units and the first in a line of connected cells that lead to higher visual centers, where our perception of vision is formed. The photoreceptors display both robust and vulnerable properties. They continue to function even after many decades of life, in spite of an exposed position where they are hit by energy-rich light for several hours each day. At the same time the photoreceptors are, for yet undefined reasons, easily disturbed and damaged by various insults, not the least by genetic stress from mutations.
Inherited retinal degenerations is a collective term relating to a large group of genetic diseases, that lead to severe vision loss or even blindness. The diseases are all caused by gene mutations, and the genes in question code for a variety of proteins with different functions, although often related to photoreceptor specific activities. Currently the number of disease genes amount to well over 100, with an even higher number of individual mutations in each of these genes (Retinal Information Network: sph.uth.edu/Retnet/, information retrieved Oct. 2012). Amongst the diseases are Retinitis Pigmentosa (RP), Leber’s Congenital Amaurosis (LCA), and Achromatopsia, which depending on the actual variant, affect between 1:3.000 – 1:30.000 individuals. Inherited retinal degenerations are today untreatable, and while individually they are rare, together they constitute a major cause of severe visual loss and blindness in the working age population (Kennan et al., 2005; Trifunović et al., 2012). This in turn has a profound impact on both the patients and the society.
The Idea
There is accumulating evidence that cyclic guanosine monophosphate (cGMP) is involved in several different types of the degenerations (Farber & Lolley, 1974; Olshevskaya et al., 2002; Trifunovic et al., 2010), and that manipulation of certain cGMP targets or components in cGMP metabolism can slow down or prevent the course of the disease (Paquet-Durand et al., 2009; 2011; Tosi et al., 2011). Compounds of the cyclic nucleotide analog class will with very high specificity affect these targets. Furthermore, depending on the chemical structure such compounds can act in either an inhibitory or stimulatory manner and hence be tailor-made to suit the exact needs of a given photoreceptor degeneration. However, the retina is shielded from unwanted molecules by the blood-retinal barrier (BRB), which is equivalent to the blood-brain barrier (BBB). To be effective in the context of photoreceptor degeneration, cyclic nucleotide analogs need to be delivered across the BRB to reach the photoreceptor cells.
The Aims of the DRUGSFORD Consortium
The idea of using cyclic nucleotide analogs to combat inherited retinal degenerations lies at the very center of the DRUGSFORD project, which is supported by the European Union 7th framework program. DRUGSFORD has as its defined goal to develop a drug and treatment regime that benefits several groups of patients suffering from these diseases. To achieve this, the consortium teams up three academic and two industrial partners, all with unique expertise and experience. The German based company BIOLOG (Bremen) is the world leading specialist in designing and producing cyclic nucleotide analogs and related compounds, and will produce novel analogs with relevant properties for counteracting the degenerations. The novel compounds will then be packaged in a drug delivery system based on the so called G-Technology® platform by the Dutch company to-BBB (Leiden). This system has previously been shown to enhance drug delivery across the BBB. The drug and delivery system combinations will be tested thoroughly on degenerating photoreceptors, using set-ups with different and increasing levels of complexity by the academic partners in Italy (Valeria Marigo, Modena), Sweden (Per Ekström, Lund) and Germany (François Paquet-Durand, Tübingen).
Perspective and Outlook
After the detailed multi-level scrutiny, manufacturing of the most promising drugs fitted to a suitable delivery system will be scaled up towards clinical-size batches and further studied towards efficacy, toxicology and off-target effects in model animals.
The results of the project will allow the two companies to further co-develop these drugs towards translation into clinical studies, addressing the high needs of RD patients and the high economic benefit of such therapies.
References
- Farber DB, Lolley RN. (1974) Cyclic guanosine monophosphate: elevation in degenerating photoreceptor cells of the C3H mouse retina. Science. 186:449-51.
- Kennan A, Aherne A, Humphries P. (2005) Light in retinitis pigmentosa. Trends Genet. 21:103-10.
- Olshevskaya EV, Ermilov AN, Dizhoor AM (2002). Factors that affect regulation of cGMP synthesis in vertebrate photoreceptors and their genetic link to human retinal degeneration. Mol Cell Biochem. 230:139-47.
- Paquet-Durand F, Beck S, Michalakis S, Goldmann T, Huber G, Mühlfriedel R, Trifunović D, Fischer MD, Fahl E, Duetsch G, Becirovic E, Wolfrum U, van Veen T, Biel M, Tanimoto N, Seeliger MW. (2011) A key role for cyclic nucleotide gated (CNG) channels in cGMP-related retinitis pigmentosa. Hum Mol Genet. 20:941-947.
- Paquet-Durand F, Hauck SM, van Veen T, Ueffing M, Ekström P (2009). PKG activity causes photoreceptor cell death in two retinitis pigmentosa models. J Neurochem. 108:796-810.
- Tosi J, Sancho-Pelluz J, Davis RJ, Hsu CW, Wolpert KV, Sengillo JD, Lin CS, Tsang SH (2011). Lentivirus-mediated expression of cDNA and shRNA slows degeneration in retinitis pigmentosa. Exp Biol Med (Maywood). 236:1211-1217.
- Trifunovic D, Dengler K, Michalakis S, Zrenner E, Wissinger B, Paquet-Durand F. (2010) cGMP-dependent cone photoreceptor degeneration in the cpfl1 mouse retina. J Comp Neurol. 518:3604-3617.
- Trifunović D, Sahaboglu A, Kaur J, Mencl S, Zrenner E, Ueffing M, Arango-Gonzalez B, Paquet-Durand F. (2012) Neuroprotective strategies for the treatment of inherited photoreceptor degeneration. Curr Mol Med. 12:598-612.
