Periodic Reporting for period 2 - IT-DED3 (Integrated Training in Dry Eye Disease Drug Development (IT-DED3))
Reporting period: 2020-01-01 to 2022-08-31
Dry eye disease (DED) is a chronic, multifactorial disease of the ocular surface and is a major and increasing healthcare problem with a serious impact on patient’s quality of life. Prevalence data reveal that 5 to 35% of the world adult’s population (3x more frequent in women) suffers from DED. 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. Experts in the field of DED stress that new and complementary therapies are needed with lesser side effects to treat an increasing and heterogenic patient population. The Integrated Training in Dry Eye Disease Drug Development (IT-DED3) has gathered world-class expertise in medicinal and 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 and 9 partner organisations. Our main objective is to accelerate new therapy and biomarker development for DED.
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.
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.
The progress of IT-DED3 beyond the state of the art is manifold. New drug targets and compound classes have been explored for DED. Several lead compounds have been tested ex vivo and in vivo. One lead compound moved further down the preclinical pipeline and was tested for formulation, safety and topical administration. A key role for corneal nociceptive pathways in the treatment of DED-related neuropathic corneal pain has been revealed. In a parallel track, bioactive compounds were extracted efficiently from natural sources with green or deep eutectic solvents and showed high potential as safe and effective potential treatment in DED. Secondly, new formulation approaches have been tested for ocular drug delivery to stabilize the tear film and for prolonged drug retention on the ocular surface.
For clinical diagnosis, several techniques (proteomic analysis of tear fluid) and new tools (activity-based probes) have been optimized and validated to identify biomarkers and allow for patient stratification. Deep learning-based methods have strongly improved image analysis, overcoming the need for manual annotation.
EXPECTED RESULTS
Several drug candidates and delivery systems have been tested in cellulo and in animal models for their PK, efficacy and safety.
Discovery of corneal nociceptive pathways and the endocannabinoid system as promising new targets for the treatment of DED and DED-related neuropathic corneal pain
Transfer of knowledge: Several patents have been filed. Knowledge and IP will be offered to interested companies for further development into a clinically applicable product.
Harmonization of patient data: a new questionnaire to phenotype DED patients in a standardized way has been established.
Contribution to clinical diagnosis of DED: novel biomarkers and imaging strategies for DED patient stratification have been developed.
We have adopted a true translational approach dedicated to patients suffering from DED and have shown to translate basic research into patient applications.
POTENTIAL IMPACT
The high prevalence and impact on quality of life of DED combined with the lack of safe and effective treatment options result in the fact that the impact of the several outcomes of IT-DED³ cannot be underestimated.
The IT-DED3 consortium 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. The scientific information gained through this project has provided new insights in the current treatment modalities proposed for DED and ocular pain, contributing to the improvement of the quality of life of DED patients. We have delivered 12 multidisciplinary trained researchers in the field of DED, 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.
For clinical diagnosis, several techniques (proteomic analysis of tear fluid) and new tools (activity-based probes) have been optimized and validated to identify biomarkers and allow for patient stratification. Deep learning-based methods have strongly improved image analysis, overcoming the need for manual annotation.
EXPECTED RESULTS
Several drug candidates and delivery systems have been tested in cellulo and in animal models for their PK, efficacy and safety.
Discovery of corneal nociceptive pathways and the endocannabinoid system as promising new targets for the treatment of DED and DED-related neuropathic corneal pain
Transfer of knowledge: Several patents have been filed. Knowledge and IP will be offered to interested companies for further development into a clinically applicable product.
Harmonization of patient data: a new questionnaire to phenotype DED patients in a standardized way has been established.
Contribution to clinical diagnosis of DED: novel biomarkers and imaging strategies for DED patient stratification have been developed.
We have adopted a true translational approach dedicated to patients suffering from DED and have shown to translate basic research into patient applications.
POTENTIAL IMPACT
The high prevalence and impact on quality of life of DED combined with the lack of safe and effective treatment options result in the fact that the impact of the several outcomes of IT-DED³ cannot be underestimated.
The IT-DED3 consortium 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. The scientific information gained through this project has provided new insights in the current treatment modalities proposed for DED and ocular pain, contributing to the improvement of the quality of life of DED patients. We have delivered 12 multidisciplinary trained researchers in the field of DED, 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.