Background and present state of the art in the research field
Retinitis Pigmentosa (RP) is a rare blinding disease with a prevalence of 1-5:10,000 that displays a strong genetic heterogeneity, with disease causing mutations identified in more than 90 genes (https://sph.uth.edu/retnet/). Nevertheless, about 30-40% of patients cannot be molecularly diagnosed because the mutation still cannot be identified. RP inheritance can be with autosomal dominant, autosomal recessive or X-linked traits. The disease is characterized by the progressive degeneration of rod photoreceptor cells, followed by a secondary loss of cone photoreceptors. Because of the anatomical distribution of rod and cone photoreceptors in the human retina, this initially results in a loss of peripheral visual field, so-called tunnel vision. Ultimately, central predominantly cone-mediated vision is also lost, resulting in complete blindness. RP patients at first experience difficulties with dark adaptation and typically are night blind. However, since human vision relies mostly on cone photoreceptors, patients may themselves not notice this at first. The loss of mid-peripheral visual field often becomes apparent in early adulthood, while blindness typically sets in during the 3rd to 4th decade of life.
The linkage of genes to RP, the identification of mutations in RP patients and the characterization of molecular events underlying the retinal degenerative process have provided ample knowledge on the causes of the disease. Nevertheless, RP still represents an area of high medical need because very few treatments are available. Critically, the progression of neurodegenerative diseases can be exceedingly slow, with often decades until the manifestation of overt symptoms, in spite of the disease relentlessly advancing. In these situations, specific biomarkers could provide for an early diagnosis that is critical to successful treatment. Moreover, in clinical studies with new drugs, such biomarkers would offer rapid efficacy readouts, a feature that is crucial in the context of slow progressing diseases, and that perhaps represents the most difficult hurdle in such drug development.
Whereas current therapeutic approaches do not account for the genetic heterogeneity of the disease, important commonalities were found in the molecular mechanism causing cell death in animal models of RP, even when the disease was caused by mutations in different genes. Neuroprotection, designed to target common molecular denominators of the degeneration process, holds high potential for the treatment of a broader cohort of patients. Partners in this proposal previously collaborated in the molecular characterization of photoreceptor cell death mechanisms in murine models of RP. We and others identified high levels of cyclic guanosine-3’-5’-mono-phosphate (cGMP) in photoreceptor cells as a trigger of cell death in several animal models of RP.
This proposal builds on from previous collaborations funded by the European Union, the EU FP7 DRUGSFORD project and the EU-H2020 MSCA-ITN-2017 transMed project, that allowed the identification of a cGMP analogue, CN03 as a compound that can protect RP mutant photoreceptors from cell death. A liposomal formulation of CN03 based on glutathione-targeted PEGylated (GSH-PEG) liposomes, called LP-CN03, was also developed. In three different mouse models of RP, this formulation enabled transfer across the blood-retinal barrier of CN03, that had protective activity on photoreceptors and significantly delayed retinal degeneration.
Objectives
The aim of this proposal is to finalize the pre-clinical development of a novel therapy for RP. We plan to develop the synthesis and pharmaceutical formulation of the LP-CN03 compound to fit the scale and quality necessary for human studies, perform pharmacokinetics (PK) and toxicology studies, identify and validate molecular targets of CN03 and identify new biomarkers in the blood. The latter will serve as surrogate biomarker for patient follow-up during the future clinical development, on the one hand, to monitor disease progression and, on the other hand, to track the response to treatment. Finally, based on the data acquired from these studies, during the last year of the project, a clinical trial protocol shall be designed for the first-in-man trial. This protocol will incorporate the latest data from PK, toxicology and biomarker studies to enable an efficient and rapid translation of the new treatment to RP patients.
Work programme
The project will be organized in three experimental work packages (WPs): 1. Pharmaceutical development of LP-CN03 synthesis and formulation, PK and toxicology studies; 2. Molecular characterisation of targets for CN03 in degenerating photoreceptor cells and identification of new biomarkers in murine and human samples based on PKG-activity; 3. Design of the clinical trial development strategy. This will be completed by two further work packages: 4. Dissemination and advocacy of the acquired knowledge; 5. Management and coordination of the project.
