To investigate therapeutic targets in human samples and mechanism of action in RED models a clinical ethics protocol was initially prepared by OSR and further defined by the other clinical partners, INS and UKK, following local regulations. Following the OSR Ethics approval the clinical study in Italy has initiated, thirteen study participants have been enrolled to date and the biological samples were collected and stored in the OSR Biobank. Local Ethics approvals are expected at the other 2 centres in INS and UKK by Q2/25. Partner INS leads on studies to develop eye drop or periocular formulations and to test the RESTORE VISION compounds for in vitro and in vivo toxicity. Review of approved ophthalmic excipients resulted in a recently published scientific manuscript. Collaboration with our subcontracting partner FAREVA enabled the development of preservative-free formulations for Spironolactone, Aprepitant, and Losartan, addressing challenges such as improving Spironolactone viscosity and overcoming Aprepitant solubility issues. For the in vivo toxicity studies, ethics committee approval has been obtained. INS conducted in vitro assays in various cell lines and proceeded with preliminary toxicity studies to screen the RESTORE VISION drugs. In vitro and In vivo models for REDs have been established at the different partner sites and new and repurposed drugs are being evaluated for therapeutic activity in RED models. MSC-EVs have been shown to enhance corneal epithelial wound healing. Application of Prima-1Met significantly inhibited corneal opacification in a pre-clinical model for EEC. Duloxetine has been tested in an Aniridia mouse model. Despite positive pre-clinical results in a 7 day model, therapeutic efficacy has not been observed with a longer treatment regime in an advanced stage of the disease with the drug concentration tested, and more pre-clinical work needs to be performed with testing of higher dosages and in an earlier stage of disease. Olisens has shown therapeutic efficacy in several pre-clinical mouse models. Additional therapeutic efficacy data have been received for topical and systemic application of Spironolactone. In OSR novel pre-clinical data for target expression for Aprepitant and Fosaprepitant indicate a potential time frame treatment window. The possible mechanism of action has already been investigated for most of the RESTORE VISION drugs. For the most promising advanced therapeutic drug candidates (stream 2a drugs), clinical studies have been designed and further promising candidates from preclinical testing (stream 2b drugs) were identified and defined at the M18 Interim results meeting on 04/12/24. In UKK and OSR clinical trial applications are anticipated in Q2/25, with applications in INS to follow regulatory advice. A project Regulatory Roadmap was developed, which identified preliminary questions to be addressed prior to an orphan drug designation (ODD) application and documented the current regulatory status of each of the RESTORE VISION drugs. Exploitation pathways will be crystallised during the course of the project but an IPR expert is already working with partner KOL to discuss IPR activities. Optimal exploitation pathways and licensing opportunities will be discussed with KOL planning a series of exploitation workshops later in the project to include all relevant parties.
