The research within the IT-DED³ consortium is divided in 3 scientific work packages (WPs) and has been performed in state of the art research facilities. First, a drug discovery WP filled the DED pipeline with new lead compounds. A preclinical drug development WP continued with the most promising compounds for upscaling, in vivo proof of concept studies, formulation and pharmacokinetics (PK) studies. In parallel, a 3rd WP focused on clinical diagnostic tools in which new biomarkers and innovative imaging techniques have been developed for patient stratification.
WP1: DRUG DISCOVERY
Within IT-DED3, different therapeutic approaches for DED treatment have been explored.
A first approach focuses on small molecules that are chemically synthesized, evaluated in vitro and optimized. This resulted in a set of lead compounds of serine protease inhibitors, free radical trapping agents and kinase inhibitors. Activity-based probes of the serine protease inhibitors have been designed for target identification in proteomic applications. The most promising representatives have moved towards WP2.
A 2nd approach focuses on compounds isolated from natural sources. Isolation and extraction methods have been optimized and concentrated compounds have been tested for their toxicity, anti-inflammatory and anti-oxidative properties and potential as drug carrier systems.
WP2: PRECLINICAL DRUG DEVELOPMENT
A multigram and stereoselective synthesis method of the most interesting serine protease inhibitors has been developed. This upscaling method is cheaper, safer and more efficient than previous methods.
Successful mucoadhesive formulations and drug delivery systems for prolonged precorneal drug retention have been established, overcoming poor solubility and stability of the natural compounds.
We have shown that cannabinoid receptor ligands demonstrate multiple therapeutic effects in DED. Tetrahydrocannabinol formulations are currently under investigation.
A simulation model for ocular PK has been generated to predict permeation and retention of drug compounds in ocular cells and tissues.
Selected compounds have been tested on different in vivo rodent models of DED. A new rat model of evaporative dry eye has been developed.
WP3: IMAGING STRATEGIES AND BIOMARKERS FOR PATIENT STRATIFICATION
The IT-DED³ search for an appropriate treatment for DED has shown that modulation of corneal nociceptive pathways may play a key role. Topical agents targeting opioid receptors were investigated in preclinical animal models of DED with promising results.
Harmonization of patient data: a new questionnaire to phenotype DED patients in a standardized way has been developed by combining existing questionnaires within IT-DED³.
Proteomics analysis to identify biomarkers in tears from healthy and DED patients has shown to be a suitable method for biomarker investigation.
Several deep learning-based methods were developed and validated to improve image analysis (infrared meibography, in vivo confocal microscopy and optical coherence tomography), showing great potential to be implemented into clinical practice in in vivo confocal microscopy images.
