Periodic Reporting for period 1 - PMSMatTrain (Novel Biomaterial-based Device for the Treatment of Progressive MS- - An Integrated Pan- European Approach)
Période du rapport: 2019-05-01 au 2021-04-30
Multiple Sclerosis is an inflammatory demyelinating disorder of the brain caused by an immune system attack on myelin and/or the cells that produce myelin and support neurons (oligodendrocytes). This leads to a widespread loss of neuronal function and deficits in executive and cognitive functions, which result in a major loss of quality of life and independence for the 2.3 million MS patients. Moreover, MS pathology is a self-perpetuating deleterious cycle of neuroinflammation and neurodegeneration that leads to protracted neuronal loss. Over time, individuals commonly enter a protracted, chronic degenerative phase of the disease, known as progressive multiple sclerosis (PMS).
Two anti-inflammatory treatments, ocreluzimab and siponimod, have recently been approved for the treatment of PMS, but less than half of individuals with PMS are suitable for these therapies. Moreover, systemic medical treatment such as these is limited by the inability of drugs to cross the blood-brain barrier.
The PMSMatTrain research programme focuses on the fundamental understanding of the interplay between neuroinflammation and neurodegeneration by using “state-of-the-art” 3D organotypic cultures, disease-relevant oligodendrocytes produced from MS patient-derived stem cells and pre-clinical models of inflammatory demyelination in the cortex. The consortium will develop novel biomaterial-based scaffolds to facilitate functional regeneration in the central nervous system. These “tuneable” hydrogels are designed for a biphasic release of anti-inflammatory molecules and neuroprotective drugs. The PMSMatTrain researchers will develop a small, minimally invasive device housing the functionalised hydrogel and proximal to the brain, which will control the phased release of a combination of candidate small-molecule drugs. Industry partners will develop the end device by providing standardised manufacturing protocols for scaled-up production and commercialisation of the final product.
Two anti-inflammatory treatments, ocreluzimab and siponimod, have recently been approved for the treatment of PMS, but less than half of individuals with PMS are suitable for these therapies. Moreover, systemic medical treatment such as these is limited by the inability of drugs to cross the blood-brain barrier.
The PMSMatTrain research programme focuses on the fundamental understanding of the interplay between neuroinflammation and neurodegeneration by using “state-of-the-art” 3D organotypic cultures, disease-relevant oligodendrocytes produced from MS patient-derived stem cells and pre-clinical models of inflammatory demyelination in the cortex. The consortium will develop novel biomaterial-based scaffolds to facilitate functional regeneration in the central nervous system. These “tuneable” hydrogels are designed for a biphasic release of anti-inflammatory molecules and neuroprotective drugs. The PMSMatTrain researchers will develop a small, minimally invasive device housing the functionalised hydrogel and proximal to the brain, which will control the phased release of a combination of candidate small-molecule drugs. Industry partners will develop the end device by providing standardised manufacturing protocols for scaled-up production and commercialisation of the final product.
The researchers based at NUI Galway have focused on hydrogels as novel therapeutic delivery platforms and successfully developed a protocol for their production and later use as a drug vehicle. Additionally, the researchers have optimised various cell culture experiments that mimic the progressive MS pathology showing how the drugs that are released from the biomaterials and affecting the “diseased cells in a dish”.
Also, to better predict the dispersion of various molecule sizes and properties within the brain a so-called in silico model has been developed which is showing the therapeutic release dynamics from this novel medical device and how it will be distributed later within the 3D brain.
At University Grenoble Alpes (UGA), another important component of the extracellular matrix has been investigated, Chondroitin Sulfate Proteoglycans (CSPGs), which promote synaptic stability in the central nervous system. A molecule that acts as a ligand for CSPGs has been identified at UGA and its therapeutic efficacy to rescue the neurite outgrowth and its possible anti-inflammatory properties are currently investigated.
In addition, lipids and proteins have also several important biological functions and play a crucial role as mediators. Therefore, the fellow at University Degli Studi Gabriele d'Annunzio di Chieti-Pescara (Ud’A) investigates the divergent expression of these molecules in pathological situations which would show putative candidates that reflect MS-like pathologies and moreover, their molecular changes after drug treatments. Ud’A has optimized two protocols, lipidomics and proteomics, which allow the analysis of thousands of lipids and proteins while keeping the spatial information of the tissues.
The fellow at Syddansk University in Denmark is developing a model system to overcome the blood-brain barrier that prevents therapeutics to reach these lesions in the brain. The first results showed inflammatory aggregates of certain immune cells. They are now investigating the role of specific chemokines in recruiting these immune cells and their roles in promoting PMS-like cortical lesions. Preliminary results are showing reduced infiltration of these cells indicate the potential protective effect of a therapeutic compound of interest.
At Westfälische Wilhelms Universität Münster (WWU), the fellows have used the technique of human induced pluripotent stem cell (iPSC). These cells are from human somatic cells that have been reprogrammed back into an embryonic-like pluripotent state that enables the development of an unlimited source of any type of human cell for research. Two cell types, oligodendrocytes and neurons, have been successfully generated to identify remyelination and neuroprotective drugs for patients with MS. Additionally, several compounds have been tested and the first results showed that several candidate drugs have been identified that had an impact on neuroprotection.
For the precise assessment of the drug release and its efficacy, the University of Antwerp (UA) is using magnetic resonance imaging (MRI) scans. A detailed protocol has been successfully developed and two prototypes of the novel medical devices have been already evaluated. Simultaneously, a complementary brain organoid model has been established from induced pluripotent stem cells (iPSC) in which the therapeutic compounds of interest will be preclinically validated for optimal dose and timing to ensure a detectable clinical benefit.
The industry partner Contipro Inc. is developing methods to incorporate the active pharmaceutical ingredients into the above-mentioned hydrogels. Different ways of solubilization were evaluated and liposomal-like structures were chosen as the most suitable vehicle. Furthermore, preliminary rheological measurements of the biomaterials were performed.
The second industry partner, Neos Surgery, is responsible for designing the outer shell for housing the delivery system. The first conceptual specifications and components of the prototypes have been successfully created. To date, three different prototype sets are developed and have been sent to the relevant partners for testing.
Also, to better predict the dispersion of various molecule sizes and properties within the brain a so-called in silico model has been developed which is showing the therapeutic release dynamics from this novel medical device and how it will be distributed later within the 3D brain.
At University Grenoble Alpes (UGA), another important component of the extracellular matrix has been investigated, Chondroitin Sulfate Proteoglycans (CSPGs), which promote synaptic stability in the central nervous system. A molecule that acts as a ligand for CSPGs has been identified at UGA and its therapeutic efficacy to rescue the neurite outgrowth and its possible anti-inflammatory properties are currently investigated.
In addition, lipids and proteins have also several important biological functions and play a crucial role as mediators. Therefore, the fellow at University Degli Studi Gabriele d'Annunzio di Chieti-Pescara (Ud’A) investigates the divergent expression of these molecules in pathological situations which would show putative candidates that reflect MS-like pathologies and moreover, their molecular changes after drug treatments. Ud’A has optimized two protocols, lipidomics and proteomics, which allow the analysis of thousands of lipids and proteins while keeping the spatial information of the tissues.
The fellow at Syddansk University in Denmark is developing a model system to overcome the blood-brain barrier that prevents therapeutics to reach these lesions in the brain. The first results showed inflammatory aggregates of certain immune cells. They are now investigating the role of specific chemokines in recruiting these immune cells and their roles in promoting PMS-like cortical lesions. Preliminary results are showing reduced infiltration of these cells indicate the potential protective effect of a therapeutic compound of interest.
At Westfälische Wilhelms Universität Münster (WWU), the fellows have used the technique of human induced pluripotent stem cell (iPSC). These cells are from human somatic cells that have been reprogrammed back into an embryonic-like pluripotent state that enables the development of an unlimited source of any type of human cell for research. Two cell types, oligodendrocytes and neurons, have been successfully generated to identify remyelination and neuroprotective drugs for patients with MS. Additionally, several compounds have been tested and the first results showed that several candidate drugs have been identified that had an impact on neuroprotection.
For the precise assessment of the drug release and its efficacy, the University of Antwerp (UA) is using magnetic resonance imaging (MRI) scans. A detailed protocol has been successfully developed and two prototypes of the novel medical devices have been already evaluated. Simultaneously, a complementary brain organoid model has been established from induced pluripotent stem cells (iPSC) in which the therapeutic compounds of interest will be preclinically validated for optimal dose and timing to ensure a detectable clinical benefit.
The industry partner Contipro Inc. is developing methods to incorporate the active pharmaceutical ingredients into the above-mentioned hydrogels. Different ways of solubilization were evaluated and liposomal-like structures were chosen as the most suitable vehicle. Furthermore, preliminary rheological measurements of the biomaterials were performed.
The second industry partner, Neos Surgery, is responsible for designing the outer shell for housing the delivery system. The first conceptual specifications and components of the prototypes have been successfully created. To date, three different prototype sets are developed and have been sent to the relevant partners for testing.
The consortium is expecting exploitation of the research results in the form of novel approaches for the treatment of neurodegenerative diseases. Within the lifetime of the project, steps involved in the research and preclinical studies will be completed. The PMSMatTrain technology would represent the first biomaterial-mediated disease-modifying therapy for the progressive phase of MS, which could facilitate the arrest of disease progression rather than offering mere symptomatic benefits. The potential translation of new therapy to the clinic could have applications as a drug delivery vehicle for other conditions, including Parkinson’s disease and Alzheimer’s disease.
Furthermore, as PMSMatTrain is a training network, it will deliver superior education to 15 early-stage researchers that will significantly enhance their future careers. The fellows will complement their research skills by gaining knowledge in multidisciplinary fields, including business, intellectual property, clinical trial design, entrepreneurship, and medical device evaluation. Equally important, the fellows will develop advanced communication skills for representing their research to varied audiences which will not only improve their writing skills but also increase awareness of the societal benefits of research.
Furthermore, as PMSMatTrain is a training network, it will deliver superior education to 15 early-stage researchers that will significantly enhance their future careers. The fellows will complement their research skills by gaining knowledge in multidisciplinary fields, including business, intellectual property, clinical trial design, entrepreneurship, and medical device evaluation. Equally important, the fellows will develop advanced communication skills for representing their research to varied audiences which will not only improve their writing skills but also increase awareness of the societal benefits of research.