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Integrated Training in Dry Eye Disease Drug Development (IT-DED3)

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

Dry eye disease (DED) is a chronic, multifactorial disease of the ocular surface and is a major and increasing healthcare problem. Prevalence data reveals that 5 to 35% of the world adult’s population suffer from DED, which is more common in an older population and is three times more frequent in women. As people are living longer, DED is becoming more prevalent. However, experts predict that the prevalence in the younger population will increase due to frequent screen usage, environmental factors and wearing of contact lenses. Currently, DED management is focused on maintaining lubrication of the ocular surface and anti-inflammatory therapy. DED experts stress that new and complementary therapies are needed with lesser side effects than established drugs to treat an increasing and heterogenic patient population. IT-DED³ has gathered world-class expertise in medicinal chemistry, process chemistry, ocular drug delivery and formulation, DED models, imaging, biomarker research and clinical ophthalmology. IT-DED³ is a multidisciplinary and intersectoral research and training network composed of 6 academic beneficiaries and one non-academic beneficiary (SME) and 9 partner organisations. Our main goal is to accelerate new therapy and biomarker development for DED. IT-DED³ will deliver 12 entrepreneurial and innovation-oriented researchers able to face future challenges in drug development in order to fill the pipeline with new therapies for DED. Besides the scientific skills, the training foresees an elaborate program of soft-skill acquisition to enhance the future career perspectives of the ESRs.
The research within IT-DED³ is divided in three scientific work packages and will be performed in state of the art research facilities. First, a drug discovery work package fills the DED pipeline with new lead compounds. A preclinical drug development work package then continues with the most promising compounds. These compounds are being upscaled and further evaluated in in vivo proof of concept studies, formulation and pharmacokinetics studies. In parallel, a third work package focuses on clinical diagnostic tools. New biomarkers and innovative imaging techniques are being developed in both animal models and in humans to allow patient stratification.

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 drug targets and compound classes are being explored for DED, leading to a new group of lead compounds for drug development. Secondly, new formulation approaches are being tested for ocular drug delivery both in an academic and industrial context. Mucoadhesive formulations will be used to stabilize the tear film and for prolonged drug retention on the ocular surface. Compounds will be tested and compared in different newly developed and validated in vivo models, allowing to select at least one optimized lead compound for an elaborate preclinical in vivo testing.

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.

POTENTIAL IMPACT

- 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.
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