Periodic Reporting for period 2 - PMSMatTrain (Novel Biomaterial-based Device for the Treatment of Progressive MS- - An Integrated Pan- European Approach)
Reporting period: 2021-05-01 to 2024-01-31
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 (oligodendrocytes) and support neurons. 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 people with MS worldwide. Moreover, MS pathology is a self-perpetuating deleterious cycle of neuroinflammation and neurodegeneration that leads to 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 particular issues being addressed by this project are an incomplete understanding of the molecular underpinnings of disease course and pathology and the sub-optimal management of the disease course. An improved understanding of the biological changes occurring in the immune and central nervous systems should help to identify novel targets for MS therapy, improve drug delivery platforms and increase the proportion of individuals that receive and are responsive to disease-modifying therapies. This is important for society as a whole, as successful MS therapies enable those living with MS to be employed for longer, placing less of a burden on healthcare systems the other family members. The overall objectives of the research carried out by members of the PMSMatTrain consortium were to do the following: 1) develop improved lab-based and pre-clinical models of MS pathology; 2) use these models to test candidate drugs that inhibit inflammation and promote the repair of damaged nerves; 3) design a novel, minimally-invasive device that targets in particular, disease in the outer layers of the brain (the cortex); 4) facilitate slow, long-term release of drugs from the device, using ‘tuneable’ bio-based hydrogels.
The researchers based at the University of Galway have successfully developed a “tuneable” hydrogel designed for biphasic release of anti-inflammatory and neuroprotective drugs. Additionally, the researchers have optimised various cell and tissue culture conditions that mimic MS pathology. They’ve demonstrated how the drugs that are released from the biomaterials impact the MS mimics. To better predict the dispersal of various molecule sizes and properties within the brain an in silico model was developed which is assisting in determining drug release dynamics from the novel medical device, and subsequent uptake into brain tissue.
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 has been investigated.
The fellow at University Degli Studi Gabriele d'Annunzio di Chieti-Pescara (Ud’A) investigated the divergent expression of lipids and proteins in pathological situations identifying putative molecular biomarkers that reflect MS-like disease and moreover, their molecular changes after drug treatments. The Ud’A team has optimized lipidomic and proteomic protocols, enabling the mapping of thousands of disease-linked lipids and proteins to different regions of brain tissue.
The fellow at Syddansk University in Denmark has developed a novel 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 within the brain. They investigated the role of specific chemokines in recruiting these immune cells and their roles in promoting PMS-like cortical lesions. Results showed 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 exploited human induced pluripotent stem cells (iPSC) to produce two human brain cell lines. 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 assist in identifying remyelination and neuroprotective drugs for patients with MS. Preliminary data showed that candidate drugs 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). A detailed protocol has been 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 are being validated for optimal dose and timing to ensure a detectable clinical benefit.
The industry partner Contipro A.S. developed 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 design has gone through 4 iterations yielding a prototypes suitable for preclinical studies. The first in-human prototype has been designed and the expected level of classification of the device has been defined.
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 has been investigated.
The fellow at University Degli Studi Gabriele d'Annunzio di Chieti-Pescara (Ud’A) investigated the divergent expression of lipids and proteins in pathological situations identifying putative molecular biomarkers that reflect MS-like disease and moreover, their molecular changes after drug treatments. The Ud’A team has optimized lipidomic and proteomic protocols, enabling the mapping of thousands of disease-linked lipids and proteins to different regions of brain tissue.
The fellow at Syddansk University in Denmark has developed a novel 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 within the brain. They investigated the role of specific chemokines in recruiting these immune cells and their roles in promoting PMS-like cortical lesions. Results showed 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 exploited human induced pluripotent stem cells (iPSC) to produce two human brain cell lines. 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 assist in identifying remyelination and neuroprotective drugs for patients with MS. Preliminary data showed that candidate drugs 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). A detailed protocol has been 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 are being validated for optimal dose and timing to ensure a detectable clinical benefit.
The industry partner Contipro A.S. developed 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 design has gone through 4 iterations yielding a prototypes suitable for preclinical studies. The first in-human prototype has been designed and the expected level of classification of the device has been defined.
The consortium is expecting exploitation of the research results in the form of novel approaches for the treatment of neurodegenerative diseases including multiple sclerosis and Alzheimer’s disease. All consortium members experienced delays in their research due to the global COVID pandemic. Progress was assisted by online planning meetings and regular virtual research meetings. Collaborations amongst consortium members are continuing after the official project end.
The PMSMatTrain training network has delivered superior education to 15 early-stage researchers that will significantly enhance their future careers. CÚRAM researchers joined a lab that was the first in Europe to be certified as 'Green' by American non-profit 'My Green Lab' (https://www.youtube.com/watch?v=9QuQ6XoEMKs(opens in new window)). In 2020, 8 PMSMatTrain researchers enrolled in the 'Green Lab Principles and Practice' 5 ECTS module, the first of its kind. Lab greening in Galway inspired SDU researchers to pursue MGL's Green Lab Certifiaction, with the lab being the first in Scandinavia to do so, in 2022. The proteomics lab in Chieti followed by gaining certification in 2023.
The PMSMatTrain training network has delivered superior education to 15 early-stage researchers that will significantly enhance their future careers. CÚRAM researchers joined a lab that was the first in Europe to be certified as 'Green' by American non-profit 'My Green Lab' (https://www.youtube.com/watch?v=9QuQ6XoEMKs(opens in new window)). In 2020, 8 PMSMatTrain researchers enrolled in the 'Green Lab Principles and Practice' 5 ECTS module, the first of its kind. Lab greening in Galway inspired SDU researchers to pursue MGL's Green Lab Certifiaction, with the lab being the first in Scandinavia to do so, in 2022. The proteomics lab in Chieti followed by gaining certification in 2023.