Periodic Reporting for period 1 - INSIGHT EU (INSIGHT FOR EYESIGHT – Novel mRNA medicines for eye disease)
Berichtszeitraum: 2019-12-31 bis 2021-02-27
Proper eyesight is essential for nearly all aspects of our life, being it reading, non-verbal communication, enjoying visual art or daily orientation. Yet, over 4 million people suffer from reduced eyesight or blindness worldwide each year with 30 million persons being blind or partially sighted in EU. Despite continuous improvements in the treatment of the underlying causes, much is still to be gained in directly treating damaged eye tissue. While the patient often suffers pain, loss of quality of life and participation in society, socio-economic costs include increased reliance on care-takers, increased healthcare cost and burden.
In this project, we envision to develop messenger RNA (mRNA)-based drugs to improve treatment of eye disease. mRNA functions as nature’s blueprint for the production of a specified protein within our cells. By delivering mRNA that encodes for a protein that possesses therapeutic properties, for instance resolving inflammation in the eye or improve healing of eye tissue, we can instruct the eye cells to produce their own medicine. Current drugs are applied via eye drops into the tear fluid that is continuously refreshed, and as a result these medicines are rapidly washed away by the tear fluid. Using Mercurna’s technology, the delivery of mRNA to cells in or around the eye will ensure that therapeutic proteins are continuously produced and released into the tear fluid over a longer period of time. Therefore, we expect our innovative strategy to be more active and cost efficient than currently used medication. Since we are able design mRNA for any existing protein, we have the possibility to target many new pathways involved eye disease that were unreachable by currently available drugs.
Mercurna has combined its expertise in the design and development of mRNA-based drugs with expertise of the Innovation Associate in the field of eye disease, to develop eye-specific treatments based on mRNA. The Innovation Associate has set-up various cell models for the eye in our laboratory, and helped to design and test new mRNAs that can be used in the treatment of various eye diseases. The results within this project demonstrate that therapeutic mRNA is suitable to treat inflammation in eye cells and recommends further investigation into the development of mRNA-based eye medication within our company.
In this project, we envision to develop messenger RNA (mRNA)-based drugs to improve treatment of eye disease. mRNA functions as nature’s blueprint for the production of a specified protein within our cells. By delivering mRNA that encodes for a protein that possesses therapeutic properties, for instance resolving inflammation in the eye or improve healing of eye tissue, we can instruct the eye cells to produce their own medicine. Current drugs are applied via eye drops into the tear fluid that is continuously refreshed, and as a result these medicines are rapidly washed away by the tear fluid. Using Mercurna’s technology, the delivery of mRNA to cells in or around the eye will ensure that therapeutic proteins are continuously produced and released into the tear fluid over a longer period of time. Therefore, we expect our innovative strategy to be more active and cost efficient than currently used medication. Since we are able design mRNA for any existing protein, we have the possibility to target many new pathways involved eye disease that were unreachable by currently available drugs.
Mercurna has combined its expertise in the design and development of mRNA-based drugs with expertise of the Innovation Associate in the field of eye disease, to develop eye-specific treatments based on mRNA. The Innovation Associate has set-up various cell models for the eye in our laboratory, and helped to design and test new mRNAs that can be used in the treatment of various eye diseases. The results within this project demonstrate that therapeutic mRNA is suitable to treat inflammation in eye cells and recommends further investigation into the development of mRNA-based eye medication within our company.
Within this project the objectives were:
1. Selecting which eye disease(s) would be suitable for mRNA-based therapy
To determine which disease would suits Mercurna’s platform the most, we performed a review of the available literature for a variety of eye diseases. In our search we took also into consideration the recommendations published by the European Vision Institute. By assessing current treatment and issues for a variety of eye diseases, taking into account recent developments in novel treatments, looking for availability of cell and animal models, and assessing the potential for mRNA-based drugs, we selected a number of diseases that stood out for their suitability for Mercurna’s purpose. These diseases were investigated in more detail to determine which therapeutic proteins would be effective to inhibit mechanism(s) that are involved in the disease progression or stimulate healing of the eye tissue. We selected a list of potentially interesting therapeutic proteins, from which we selected the most promising for mRNA design and synthesis.
2. Establishing cell models of the physiological eye in healthy or diseased state to test mRNA-based drugs
Since inflammation plays in important role in the selected eye diseases, cell models were developed in which we incubated cells of the outer layer of the eye with natural components which induce inflammation alike what happens in the actual disease. We also imitated drying out of the eyes by exposing the outer side of the cells for a certain period to air, which results in an inflamed response of these cells. For all models, optimal conditions were determined and assays to detect inflammatory molecules produced by these cells were established. We could successfully demonstrate that inflammation was induced within the optimized conditions. Next to the “simplified” model of culturing an eye cell layer in 2D, we also collaborated to set-up a more advanced system in which multiple types of cells that form the cornea are cultured in 3D using experimental conditions that resemble blinking and subsequent drainage of tear fluid as it would happen under physiological circumstances. This 3D model will represent the physiological conditions as close as currently possible, and will provide us with information about Mercurna’s mRNA platform that can much better be translated to patients.
3. Selecting one or more mRNAs that could be used for therapy of the selected disease(s)
Based on the study presented under objective 1, we selected several proteins with a high therapeutic potential in the eye diseases we had chosen. Since small variations in an mRNA molecule can have a significant impact on its performance, it is important to determine which version is the most optimal. Therefore, we designed different versions of selected therapeutic mRNAs based on Mercurna’s design rules, and synthesized these mRNAs using Mercurna’s in-house facility. Therapeutic mRNAs were tested in cell models for their performance, and the mRNA version that induced the highest production of the therapeutic protein was chosen for further testing in more complex eye models.
4. Determining if Mercurna’s delivery platform can be used in its current state or should be adapted for application in eye disease
After selecting the best performing mRNAs, we determined the efficacy of these in one of our verified cell models for eye inflammation. So far, we have been able to show that the delivery of our therapeutic mRNA diminishes production of one of the factors that functions as an indicator for inflammation. Currently, we are other indicators to fully demonstrate the effect of our therapeutic mRNA. In addition, we are designing and testing improved versions of our delivery system that are optimized for application in the eye.
1. Selecting which eye disease(s) would be suitable for mRNA-based therapy
To determine which disease would suits Mercurna’s platform the most, we performed a review of the available literature for a variety of eye diseases. In our search we took also into consideration the recommendations published by the European Vision Institute. By assessing current treatment and issues for a variety of eye diseases, taking into account recent developments in novel treatments, looking for availability of cell and animal models, and assessing the potential for mRNA-based drugs, we selected a number of diseases that stood out for their suitability for Mercurna’s purpose. These diseases were investigated in more detail to determine which therapeutic proteins would be effective to inhibit mechanism(s) that are involved in the disease progression or stimulate healing of the eye tissue. We selected a list of potentially interesting therapeutic proteins, from which we selected the most promising for mRNA design and synthesis.
2. Establishing cell models of the physiological eye in healthy or diseased state to test mRNA-based drugs
Since inflammation plays in important role in the selected eye diseases, cell models were developed in which we incubated cells of the outer layer of the eye with natural components which induce inflammation alike what happens in the actual disease. We also imitated drying out of the eyes by exposing the outer side of the cells for a certain period to air, which results in an inflamed response of these cells. For all models, optimal conditions were determined and assays to detect inflammatory molecules produced by these cells were established. We could successfully demonstrate that inflammation was induced within the optimized conditions. Next to the “simplified” model of culturing an eye cell layer in 2D, we also collaborated to set-up a more advanced system in which multiple types of cells that form the cornea are cultured in 3D using experimental conditions that resemble blinking and subsequent drainage of tear fluid as it would happen under physiological circumstances. This 3D model will represent the physiological conditions as close as currently possible, and will provide us with information about Mercurna’s mRNA platform that can much better be translated to patients.
3. Selecting one or more mRNAs that could be used for therapy of the selected disease(s)
Based on the study presented under objective 1, we selected several proteins with a high therapeutic potential in the eye diseases we had chosen. Since small variations in an mRNA molecule can have a significant impact on its performance, it is important to determine which version is the most optimal. Therefore, we designed different versions of selected therapeutic mRNAs based on Mercurna’s design rules, and synthesized these mRNAs using Mercurna’s in-house facility. Therapeutic mRNAs were tested in cell models for their performance, and the mRNA version that induced the highest production of the therapeutic protein was chosen for further testing in more complex eye models.
4. Determining if Mercurna’s delivery platform can be used in its current state or should be adapted for application in eye disease
After selecting the best performing mRNAs, we determined the efficacy of these in one of our verified cell models for eye inflammation. So far, we have been able to show that the delivery of our therapeutic mRNA diminishes production of one of the factors that functions as an indicator for inflammation. Currently, we are other indicators to fully demonstrate the effect of our therapeutic mRNA. In addition, we are designing and testing improved versions of our delivery system that are optimized for application in the eye.
We envisioned to improve the treatment of eye disease by delivering mRNA that encodes for a protein that possesses therapeutic properties, for instance resolving inflammation in the eye or improve healing of eye tissue. Within this project we have determined the most suitable eye diseases for mRNA-based therapy and selected several potential therapeutic mRNAs that can be applied. Importantly, we have successfully applied the first therapeutic mRNA in one of our cell models and demonstrated its efficacy. The results from this project will form the basis to further optimize Mercurna’s technology for therapeutic application in eye diseases, and warrants testing of other potentially interesting therapeutic mRNAs. Our technology will ensure that therapeutic proteins are continuously produced and released into the tear fluid over a longer period of time, which will improve treatment compared to current drugs that are applied via eye drops and are rapidly washed away by the tear fluid. We expect that our innovative strategy to be more active and cost efficient than currently used medication, and will offer the possibility to target many new pathways involved eye disease that were unreachable by currently available drugs.