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Educational Network in Ocular Drug Delivery and Therapeutics

Periodic Reporting for period 2 - OcuTher (Educational Network in Ocular Drug Delivery and Therapeutics)

Reporting period: 2018-11-01 to 2020-10-31

Ocular drug therapy, especially the treatment of diseases affecting the posterior eye segment, is hampered by the ineffective drug delivery to the target sites. Therefore, development of drugs against age-related macular degeneration, glaucomatous retinal degeneration, diabetic retinopathies and inherited retinal degenerations has been slow, and most retinal diseases are still without pharmacological treatments. Lack of treatments is related to the problems of drug delivery and lack of systematic tools for ocular drug development. OCUTHER brings together all the necessary expertise for preclinical development of retinal drug treatments, including chemistry, drug delivery system design, experimental and computational pharmacokinetics, and ophthalmology. The project integrates together combined efforts of 9 beneficiaries from academia and industry, 2 academic, and 7 non-academic partner organisations. Our objectives are to develop new experimental and computational tools for ocular drug development, and test new potential regenerative treatments for retinal diseases, including both drugs and novel delivery systems. OCUTHER will train the next generation of scientists in this field by offering an extensive joint training programme to 15 ESRs. The project focuses on promoting scientific excellence and exploits the specific research and commercial expertise and infrastructure of the OCUTHER network as a whole. The exposure to all elements of ocular drug development enables OCUTHER to translate expertise from all disciplines to the ESRs and educate the future scientists in the field of ocular drug development.
The research within the OCUTHER consortium can be divided into three work packages. First, tools for ocular drug and delivery system design and testing is developed. Secondly, drug delivery systems are designed and tested for their pharmaceutical properties. Third, the biological properties of the delivery systems and drug candidates are being tested with preclinical models. The target diseases are retinal pathologies, which are treated in the experiments using drug administration into the vitreous of the eye, blood stream and surface of the eye. The project has progressed at all levels.

A range of different experimental and computational methods have been developed to augment ocular drug development. This includes pharmacokinetic non-invasive fluorescence methods to monitor drug and delivery system kinetics in the eyes, methods set up for the studies of expression proteins that may affect ocular distribution and elimination of drugs. Furthermore, the model structures and related mathematics of have been generated for ocular pharmacokinetics. Importantly, we have determined the dose scaling factors for intravitreal drug administration between rat, rabbit and human. The work towards pharmacodynamic test methods so far includes cell model work on autophagy in age-related macular degeneration, and methods for measuring retinal inflammation and immunological responses.

Pharmaceutical development of drug delivery systems has progressed in many respects. Delivery systems have been generated based on many technologies, including prolonged action gels, soluble polymeric conjugates, magnetic nanoparticles for topical administration, ultrasound activatable systems for targeted drug release, and nano-sized polymeric assemblies, liposomes and protein cages for cellular drug targeting. The studies have been concentrated so far on optimization of pharmaceutical properties, such as size, charge, stealth-coating , labeling, stability and drug loading to the particles. Some delivery systems have shown prolonged release, promising dosing intervals of even a year. On the other hand, some pullulan conjugates showed cell specific delivery in the retina.

Biological testing of drug delivery materials has been done using toxicological cellular methods and in some cases mobility and interactions of the particles have been investigated using ex vivo vitreal models. Polymeric assemblies (micelles, polymersomes, conjugate, magnetic nanoparticles) have been studied also in vivo in rats and rabbits and they showed prolonged retention in the vitreous after injection. New drug candidates and delivery methods have been tested using cellular methods. For example, VCP inhibitors demonstrated neuroprotective effects in retinal explant cultures.

Overview of the results. OCUTHER project has generated generalizable results that are useful for ocular drug developers at international scale (e.g. enzyme activities, kinetic parameters in different species). Furthermore, the tools of OCUTHER project will be utilized in drug development, such as inter-species dose scaling factors and pharmacokinetic models. We have developed several ocular drug delivery systems that are promising for the delivery of poorly soluble drugs, retinal cell based targeting and prolonged action and longer drug dosing intervals. New drugs for the retinal regeneration have been investigated and their efficacy was improved with the delivery systems. The project consortium includes many companies that offer potential avenues for further exploitation. Project results have been disseminated in various conferences, public events, newsletters and publications.
The following progress beyond the state of the art has been made:

Technology for prolonged vitreal retention of polymersomes and polymeric drug conjugates after intravitreal injections.
Role of endoplasmic reticulum associated protein degradation was shown in the loss of photoreceptors.
Neuroprotective activity of VCP inhibitors in retinal tests and their formulation in micellar formulations.
Successful synthesis of pullulan conjugates and cell specific distribution to the retina.
Generation of magnetic nanoparticles and demonstration magnetic movement of the particles in the rat eyes.
Prolonged delivery of bevacizumab from gel formulation over several months, even a year.
Characterization of ocular drug metabolizing enzymes in the rabbit and pig eye.
Cellular siRNA delivery with virus mimic nanoparticles.
Predictable ocular computer models for the kinetics of drugs and delivery systems.

Potential impact

First and foremost, a new generation of researchers will be educated who have a comprehensive understanding of the requirements for successful ocular drug development. These researchers will be of great importance for the pharmaceutical industry in boosting innovation and to develop more effective ocular drug products. Secondly, a number of highly interesting ocular drugs and delivery systems will be produced that will be ready for (pre)clinical testing. Thirdly, integrated experimental and computational tools will facilitate the development of ocular drugs in the pharmaceutical industry. The interaction with the industrial partners within the consortium facilitates the transfer of knowledge and facilitates further development at the end of the OCUTHER program.
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OcuTher consortium_Kick-off conference 2017