Periodic Reporting for period 1 - IT-DED3 (Integrated Training in Dry Eye Disease Drug Development (IT-DED3))
Reporting period: 2018-01-01 to 2019-12-31
WP1: DRUG DISCOVERY
Within IT-DED³, different therapeutic approaches for DED treatment are being explored.
- Small molecules: a first approach focuses on small molecules that are chemically synthesized and optimized. A first set of lead compounds include the serine protease inhibitors, radical trapping agents and kinase inhibitors. Chemical libraries have been synthesized and are being evaluated in vitro. Activity based probes of the serine protease inhibitors have been designed for target identification. The most promising representatives of each chemical class will move towards work package 2.
- Natural compounds: a second approach focuses on compounds isolated from natural sources. Isolation and extraction methods are optimized and concentrated compounds are tested for their toxicity, anti-inflammatory and anti-oxidative properties and potential as drug carrier systems.
WP2: PRECLINICAL DRUG DEVELOPMENT
- Upscaling: a multigram synthesis scheme of the most interesting lead compound has been developed.
- Formulation: for the natural compounds, two formulation strategies (liposomes and cyclodextrins) have been tested and optimized to overcome their poor solubility and stability. In vitro characterization of these formulations is planned for the second term of the project. Together with two industrial partners, several lead compounds are being formulated in innovative drug delivery systems.
- Ocular pharmacokinetics: data and tools have been generated to predict permeation and retention of drug compounds in ocular cells and tissues and will be implemented on the compounds provided by the IT-DED³ consortium. In addition, determination of the surface retention of carrier/delivery systems is under development.
- In vivo models: a new rat model of evaporative dry eye (cauterization of meibomian glands) has been developed for the in vivo proof of concept testing of the selected compounds.
WP3: IMAGING STRATEGIES AND BIOMARKERS FOR PATIENT STRATIFICATION
The IT-DED³ search for an appropriate treatment for DED has currently shown that modulation of corneal nociceptive pathways may play a key role in the treatment of DED. Topical agents targeting this pathway are currently under investigation in several preclinical animal models of DED.
- Harmonization of patient data: a new questionnaire to phenotype DED patients in a standardized way within the IT-DED³ consortium has been developed by combining existing questionnaires within the network and will be of great value for the second part of the project and beyond in terms of collection of large datasets from DED patients.
- Search for new biomarkers: tears from healthy and DED patients have been collected and will undergo a proteomics analysis to identify biomarkers.
- Imaging strategies for patient stratification: algorithms to quantify changes in optical coherence tomography data from DED examinations have been developed and are being translated into clinical devices together with an industrial partner from the IT-DED³ consortium.
New optical and molecular biomarkers are being identified by new techniques, such as optical coherence tomography and confocal microscopy. We adopt a true translational approach dedicated to patients suffering from dry eye disease and intend to translate basic research into patient applications.
RESULTS EXPECTED FOR THE END OF THE PROJECT
- Several drug candidates and delivery systems will be tested in cellulo and in animal models for their pharmacokinetics, efficacy and safety.
- Transfer of knowledge: at least one drug candidate/carrier will be offered to companies for further development into a clinically applicable product.
- A genomic-based systematic screening approach will have been performed in DED patients.
- Biomarkers and imaging strategies for DED patient stratification.
- Because of the high prevalence of DED, the high economic and quality of life impact, and the lack of safe and effective treatment options, the potential impact of the outcomes of IT-DED³ cannot be underestimated.
- IT-DED³ has a holistic bench-to-bedside approach and intends to go from R&D to proof of concept with a patient- and disease-driven mind set. IT-DED³ overcomes the fragmentation of drug discovery and development approaches often seen in an academic context.
- IT-DED³ will deliver a team of 12 multidisciplinary researchers in the field of DED, hence injecting a new generation of excellent scientists into academia and pharmaceutical industry to speed up innovation and new treatments in the field of DED and ocular diseases in general.