Speaker: Dr. Andrés Miguez González, Principal Investigator, Clinical Neuroimmunology Lab, Vall d'Hebron Research Institute (VHIR). Multiple Sclerosis Centre of Catalonia (Cemcat). CIBER of Neurodegenerative Diseases (CIBERNED)

Abstract: Multiple sclerosis (MS) is the leading cause of non-traumatic disability in young adults, affecting nearly 3 million people worldwide, with a mean age at diagnosis of 32 years. It is a chronic autoimmune disease of the central nervous system (CNS) characterized by inflammation, demyelination and neurodegeneration. Current MS therapies are highly effective in controlling peripheral immune-mediated inflammation, but have consistently failed to adequately target the CNS-intrinsic mechanisms underlying neurodegeneration and disease progression, which are thought to involve glial cells such as microglia, astrocytes and oligodendrocytes. Recent technological advances have revealed the functional heterogeneity of these glial cells in MS, highlighting their crucial roles in neuroinflammation, demyelination and remyelination.
The lack of robust preclinical models based on human cells and tissues remains a major bottleneck for the translation of neuroprotective and remyelinating therapies in MS. To overcome this limitation and investigate the role of human glial cells in MS pathogenesis and progression, Dr. Andrés Miguez has developed New Approach Methodologies (NAMs) using a series of induced pluripotent stem cell (iPSC)-based humanized preclinical models: (i) In vivo human-mouse chimeras; (ii) Ex vivo human brain slice remyelination cultures; (iii) In vitro human myelination assays on engineered nanofibers.
Alterations identified to date in these MS humanized models correlate with patient disability, highlighting glial-intrinsic dysfunction as a potential driver of clinical progression in MS. Ongoing single-cell spatial transcriptomics will provide deeper insights into differentially expressed genes in human oligodendrocytes and astrocytes across the disease course. Based on these data, small-molecule compounds able to modulate the expression of disease-associated genes will be selected and tested as potential neuroprotective and remyelinating therapies.

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