DRUGSFORD-bis: Towards a clinical trial for hereditary retinal degeneration

01.12.2016 bis 31.12.2017

Inherited retinal degeneration (RD) is a devastating and currently untreatable neurodegenerative disease, which still lacks suitable molecular targets for therapeutic interventions. A major challenge for therapy development lies in the high genetic heterogeneity of RD, with disease-causing mutations in over 250 different genes. A second major challenge is the blood-retinal-barrier (BRB), which prevents pharmacological compounds from reaching the neuroretina. In the EU-funded DRUGSFORD project (www.drugsford.eu), these challenges were addressed by targeting cGMP-signaling as a disease driver common to many different types of RD and by combining pharmacological therapy with an innovative liposomal drug delivery system (DDS) designed to facilitate transcytosis across the BRB.
DRUGSFORD has produced a lead compound product, which is a combination of the inhibitory cGMP analogue DF003 and the liposomal DDS, and referred to by the code name LP-DF003. LP-DF003 was efficiently targeted to the neuroretina and has shown pre-clinical in vivo efficacy in three different animal models for RD with no obvious toxicity in systemic and local application. The data shown in Figure 1a and 1b illustrates how LP-DF003 increased survival of rod photoreceptors in one of the three RD models used, the rd10 mouse. Most importantly, LP-DF003 treatment completely preserved the function of rd10 cone photoreceptors (Figure 1c-f), highlighting its strong potential for RD treatment.
All in all, DRUGSFORD has introduced cyclic nucleotide analogues, such as DF003, as a new class of compounds for RD treatment, combined with an innovative retinal delivery method, which together show considerable promise for a successful clinical translation. A patent for the use of LP-DF003 was filed on 17th March 2015 (EP15159285.4), with the corresponding PCT application filed on 16th March 2016. Furthermore, LP-DF003 obtained an orphan drug designation (ODD) from the European Medicines Agency on 19th March 2015 (EU/3/15/1462). The Swedish company SP Process Development (SPPD) has established a production process for the manufacturing of clinical grade (GMP) LP-DF003. In parallel, a pre-clinical toxicological assessment in non-human primates (NHP) subcontracted to the company Covance did not reveal any major test item related adverse effects. LP-DF003 has thus successfully cleared all major steps of pre-clinical development for the treatment of RD. Since the DRUGSFORD project ended on 31st August 2016, at this point, funding is requested to continue this fruitful work and allow for the preparation of corresponding clinical trials.