Research Inez Wens

Abstract

Multiple sclerosis (MS) is an inflammatory neurodegenerative disease of the central nervous system for which no cure is available. It is the leading cause of non-traumatic disabling neurological disease in young adults with more than 6.500 people affected in Flanders. Since MS strikes during the primary productive time of one's personal and professional life, it leads to a major physical and socio-economic burden to the patient, family, and society. Therefore, new therapeutic interventions with improved efficacy over existing drugs and good tolerability are needed. As chronic inflammatory processes drive the neurodegeneration, we hypothesize that improved clinical outcome depends on restoring the balance between inflammation and the remaining capacity of neuronal self-renewal. Therefore, cell therapy that specifically targets the damaging immune reactions that cause MS and induce disease-specific tolerance without affecting protective immunity against pathogens and cancer is a promising approach. Recently, a collaborative network of European centers joined efforts to bring antigen-specific therapy for MS to the clinic. Two single-center phase I clinical trials evaluating the use of antigen-specific tolerance-inducing dendritic cells (tolDC) in MS patients were conducted (previously funded by IWT- TBM and H2020). No serious adverse events were observed. Next, we aim to demonstrate efficacy of tolDC treatment in a phase II clinical trial in patients with MS. Coordinated patient and MRI monitoring, including radiological correlates of neurodegeneration, and immunomonitoring will enable us to demonstrate efficacy of tolDC administration and to support future efforts in the field of MS therapy. An effective therapy that lowers morbidity with reduced occurrence of side effects and less frequent hospitalizations will enhance quality of life of patients as well as dramatically reduce economic burden. This would represent a breakthrough for healthcare in MS.

Researcher(s)

• Promoter: Cools Nathalie
• Co-promoter: Wens Inez

Research team(s)

• Laboratory for Experimental Hematology (LEH)

Project type(s)

• Research Project

Abstract

Multiple sclerosis (MS) is a neurodegenerative disease of the central nervous system (CNS), characterized by inflammatory attacks against the myelin sheath. Today, over 10 disease-modifying therapies are approved, predominantly focusing on immunomodulation. However, remyelination remains a major unmet clinical need in (progressive) MS therapy. Today, efforts are made to unravel de- and remyelinating mechanisms. Therefore, brain-derived neurotrophic factor (BDNF) seems an interesting protein, as it promotes neuroprotection and (re)myelination. Interestingly, BDNF levels are reported to be reduced in MS. While neurons are the principal source of BDNF in the CNS, key-immune cells can also secrete BDNF, suggesting that BDNF mediates the cross-talk between the immune- and nervous system. Recently, a growing body of research underscoring the key role of regulatory T cells (Treg) in MS, has emerged. Interestingly, a novel pro-regenerative function of Treg was revealed, mediated by the secretion of pro-myelinating factors. Nevertheless, the relation between immune cell-mediated BDNF expression and its accompanying effects in the CNS, such as remyelination, remains elusive in MS. Therefore, we aim to investigate the influence of immune cell-induced BDNF expression on remyelination using state-of-the-art techniques and patient samples. Our findings may result in the development of novel strategies to improve remyelination, predominantly focussing on progressive MS treatment.

Researcher(s)

• Promoter: Cools Nathalie
• Co-promoter: Wens Inez
• Fellow: El Ouaamari Yousra

Research team(s)

• Laboratory for Experimental Hematology (LEH)

Project type(s)

• Research Project

Abstract

The ultimate goal of this research project is to develop a clinically safe and regenerative cell-based vaccine for the treatment of (progressive) multiple sclerosis (MS), since remyelination remains a major unmet need. We recently succesfully developed "designer" Tregs that are engineered to express high levels of BDNF. Here, we are ready to assess the remyelinating capacity of these transgenic Tregs, hypothesizing that these Tregs will excel in their pro-regenerative properties, driving oligodendrocyte differentiation and remyelination, beyond immunomodulation. This would represent a breakthrough for MS healthcare.

Researcher(s)

• Promoter: Wens Inez

Research team(s)

• Laboratory for Experimental Hematology (LEH)

Project type(s)

• Research Project

Abstract

The general goal of this research project is to develop a clinically safe cell-based vaccine for the treatment of (progressive) MS, based on BDNF-expressing Tregs. By using state-of-the art techniques, we will develop "designer" Tregs that are engineered to express high levels of BDNF. We hypothesize that these Tregs will excel in their pro-regenerative properties, driving oligodendrocyte differentiation and remyelination, beyond immunomodulation with the aim to induce remyelination in MS.

Researcher(s)

• Promoter: Wens Inez
• Co-promoter: Cools Nathalie

Research team(s)

• Laboratory for Experimental Hematology (LEH)

Project type(s)

• Research Project

Abstract

Cell therapy is one of the most promising future clinical options in the medical arsenal for the treatment of patients suffering from serious conditions where unmet medical needs exist. Breakthroughs in cell and molecular biology have enabled the development of cell-based vaccines, and to date cell therapies are being evaluated in the first clinical trials aiming to treat autoimmune diseases, including multiple sclerosis (MS). Although the therapeutic landscape of MS is constantly evolving, none of the currently available treatments results in a permanent stabilization of the disease, and most of them indiscriminately suppress the immune system. In this perspective, immune-modulatory cell therapy has the potential to target underlying disease mechanisms in a more specific way. In particular, regulatory T cells (Tregs) offer the opportunity to target cells that are potentially involved in the induction and progression of the disease. In current proposal, we aim to develop TCR-engineered Tregs to enforce their interaction with cells that are key in the disease pathogenesis. In doing so, we ultimately aim to control autoimmunity.

Researcher(s)

• Promoter: Cools Nathalie
• Co-promoter: Wens Inez

Research team(s)

• Laboratory for Experimental Hematology (LEH)

Project type(s)

• Research Project

Abstract

The therapeutic landscape of MS is constantly evolving, and one could pose the question if we still have unmet needs for the treatment of MS? Nevertheless, despite the availability of improved therapies and the significant advances in the understanding of what triggers disease, patients continue to experience relapses and, in some cases, are exposed to potential life-threatening side-effects. Hence, current challenge is to balance the need to modify the underlying disease pathogenesis and the long-term risks. In this perspective, immunemodulatory cell therapy has brought a new hope for a wide spectrum of diseases. Tregs offer the opportunity to target cells that are potentially involved in the disease progress. Nevertheless, whether Tregs act in an antigen-specific manner remains elusive. Hence, despite the potential that Treg therapy holds, 2 there are still some challenges, not in the least to direct the interaction of Tregs with key disease-associated immune cells in an antigen-specific manner. To address these, the following objectives have been set forth in current project proposal: Our first objective is to select antigen-specific effector T cells by means of tetramer analysis, thereby identifying and cloning a myelin-recognizing TCR. Secondly, we will optimize a clinically safe mRNA electroporation protocol to induce expression of mRNA encoding the TCR in freshly-isolated and expanded Tregs from MS patients. Thirdly, we ensure the stability of the phenotype and suppressive function of TCR-engineered Tregs. In doing so, we will deliver in vitro proof-of-concept of the safety of the approach which is especially important when administering the cells in an inflammatory disease-driven microenvironment. Finally, we will investigate if TCR-transgenic Tregs can modulate ongoing disease processes by investigating their effect on the phenotype and function of DCs from healthy volunteers and MS patients. Ultimately, we envisage that this will foster a durable clinical application of this technology without the risk for general immunosuppression.

Researcher(s)

• Promoter: Cools Nathalie
• Co-promoter: Wens Inez
• Fellow: Janssens Ibo

Research team(s)

• Laboratory for Experimental Hematology (LEH)

Project type(s)

• Research Project