Myelin regeneration: from gene therapy to energy metabolism

Speaker: Dr. Vanja Tepavcevic
Institution: Departamento de Neurociencias, Facultad de Medicina y Enfermería, Universidad del País Vasco. Leioa, Spain
Place: CIPF conference room

Abstract: Multiple sclerosis (MS), a chronic demyelinating disease of the central nervous system (CNS), is the leading cause of acquired neurological disability in young adults. Current treatments are immunomodulatory and provide temporary relief during relapses, but mostly lack an effect on disability progression, caused by axonal degeneration. Remyelination (myelin repair) of demyelinated axons reduces axonal degeneration in mice and patients, but this process eventually fails with disease progression. Thus, promoting remyelination in MS is a potential therapeutic strategy to prevent irreversible neurological deficits. So far, the search for pro-remyelinating agents has focused primarily on compounds that promote differentiation of oligodendrocyte progenitor cells (OPCs), the remyelinating cells of the CNS, thus generation of new oligodendrocytes. Yet, clinical trials performed have shown modest functional benefits and scarce impact on the clinical outcome. In this talk, I will we argue that achieving clinical benefits in patients with MS will likely require complementary/alternative approaches to stimulate remyelination. I will present our recently published data on gene therapy as a therapeutically relevant strategy for stimulating OPC repopulation of demyelinating lesions that, as I will show, fails in the disease. Then, I will present our ongoing work based on the hypothesis that remyelination in MS fails due to metabolic deficit that prevents OPCs from synthesizing new myelin.

12:00 – 12:30 Gergana Mincheva

Extracellular vesicles from mesenchymal stem cells reverse neuroinflammation and cognitive and motor impairment in rats with mild liver damage

Cirrhotic patients may develop minimal hepatic encephalopathy (MHE), with mild cognitive impairment, psychomotor slowing and motor incoordination. Human mesenchymal stem cells derived extracellular vesicles (MSC-EVs) have been proposed as therapy for different diseases due to their immunomodulatory, anti-inflammatory and regenerative properties. The aim of this study was to assess if MSC-EVs reverse cognitive and motor impairment in rats with mild liver damage and identifying the underlying mechanisms. Mild liver damage was induced by intraperitoneal injection of CCl4 during four weeks. MSC-EVs were isolated from human adipose tissue-derived stem and were injected intravenously. We assessed cognitive and motor impairment with different behavioral tests, neuroinflammation and neurotransmission alterations were assessed by immunohistochemistry and Western Blot. MSC-EVs injected intravenously reduce neuroinflammation in hippocampus and cerebellum and reverse cognitive and motor impairment in rats with mid liver damage. This suggests that MSC-EVs are a promising therapy which could be used to improve MHE and the quality of life in cirrhotic patients.

12:30 – 13:00 Irene Soler

Unveiling transcriptomic sex differences of multiple sclerosis: an in silico atlas across cell types analysing scRNA-seq and snRNA-seq data

 Multiple sclerosis (MS) is the leading cause of nontraumatic disability in young adults. Its major hallmark is myelin damage in the central nervous system, resulting in chronic neuroinflammation and neurodegeneration. Sex differences in the incidence, prevalence, disease progression, symptom variability, and response to treatment of MS have been reported. However, the molecular mechanisms underlying these differences remain poorly understood. The aim of this work is to exhaustively characterize sex bias in MS by cell type. To this end, we performed an in silico analysis of scRNA-seq and snRNA-seq data using the R programming language. First, we performed a systematic review in public repositories following the PRISMA guidelines. Three datasets were identified, each representing a different MS subtype. Then, we processed each selected dataset independently. After the annotation of the different cell types, all of them were fully characterized with the following analyses: differential gene expression, functional profiling, signaling pathways and cell-cell communication. In this seminar, we will focus on the secondary progressive MS subtype in nervous tissue, where the results obtained for astrocytes, microglia, neurons, oligodendrocytes, and oligodendrocyte precursor cells will be addressed

12:00 – 12:30 Milagros Buffa

Targeting MCL-1 and BOK Interaction: Hit Compound Optimization and Mechanistic Insights for Cancer Therapy

Finding new cancer therapies is critical to improve treatment options and increasing patient survival. Dr. Mar Orzaez’s laboratory has discovered a hit compound for a new therapeutic target. In the outer mitochondrial membrane, induced myeloid leukemia cell differentiation protein (MCL1) and BCL2-related ovarian killer (BOK) interact through their transmembrane domains. Our hit compound, MBoIN 179, disrupts this interaction and releases BOK to induce cell death. To optimize the structure of our compound and learn more about its mechanism of action, we are performing several structural studies. Additionally, as a high overexpression of MCL-1 has been observed in lung tumours, we are performing functional experiments on 2D and 3D lung cancer models with our hit compound, to highlight the potential cell death effect of MBoIN 179.