Fatty acid elongase (ELOVL) targeting to promote remyelination and central nervous system repair in multiple sclerosis

Overview

This research program targets fatty acid elongases (ELOVLs), particularly ELOVL6, as a strategy to promote remyelination and repair in multiple sclerosis (MS). Prior work by the team identified SCD1, a fatty acid desaturase, as a driver of the shift from repair-promoting phagocytes to inflammatory, lipid-laden foamy phagocytes in MS lesions. While SCD1 inhibition showed therapeutic potential, severe side effects in preclinical models limited its clinical applicability. ELOVLs act downstream of SCD1 by elongating its fatty acid products, offering a more targeted intervention point. Knockout of ELOVL6 has demonstrated reduced intracellular lipid accumulation in macrophages and microglia, decreased inflammatory mediators, and increased remyelination in both ex vivo brain slice cultures and in vivo mouse models of demyelination.

Technical specifications

Key findings and approach:

• Ex vivo organotypic cerebellar brain slice cultures demyelinated with lysolecithin showed reduced lipid load in macrophages and microglia and increased myelin-axon colocalization in ELOVL6 knockout slices compared to wild-type controls
• In vivo cuprizone-induced demyelination model demonstrated greater myelination after demyelination and during spontaneous remyelination phases in ELOVL6 knockout mice, confirmed by myelin staining and g-ratio analysis
• Reduction of inflammatory mediators observed in ELOVL6 knockout models, supporting an anti-inflammatory effect alongside remyelination
• Planned overexpression screening of ELOVLs 1 through 7 in bone marrow-derived macrophages to assess inflammatory response, metabolic changes, and central nervous system repair effects
• Future testing of ELOVL6 inhibitors and investigation of additional cell types such as oligodendrocytes

Technology readiness level

The research is currently at the preclinical validation stage, with proof-of-concept demonstrated in ex vivo brain slice cultures and in vivo mouse cuprizone models. Further validation is needed, including testing of pharmacological ELOVL6 inhibitors, assessment of blood-brain barrier penetration strategies, and expanded screening of other ELOVL family members. The program is positioned for collaborative development to accelerate translation toward therapeutic candidates for MS.