A protein leads to nerve fiber and myelin damage, particularly in progressive forms of multiple sclerosis, by activating brain immune cells called microglia, according to a new study. Its researchers also noted this protein is the target of experimental MS treatment called temelimab (GNbAC1), which showed potential in Phase 2 clinical trials.
The research, “pHERV-W envelope protein fuels microglial cell-dependent damage of myelinated axons in multiple sclerosis,” was published in the journal Proceedings of the National Academy of Sciences (PNAS).
Nerve fiber (axonal) degeneration is recognized as the main contributor to clinical disability and disease progression in MS.
The involvement of microglia — important cells in a first response to infection in the central nervous system — has been reported through their M1 profile that leads to the production of proinflammatory molecules, as well as the observed relationship between the activation of these cells and disability in progressive MS.
In contrast, the M2 profile (phenotype) of microglia can be neuroprotective via the clearance of myelin debris, which is essential for remyelination — the production of new myelin, the protective coat of neurons that is destroyed in MS.
A team from GeNeuro (the developer of temelimab) and researchers at institutions in Germany, Canada, and the U.S. had previously shown that the MS-associated human endogenous retroviruses envelope protein, or pHERV-W ENV, suppresses myelin repair. That is, it works to prevent the formation of new myelin sheaths, which protect nerve fibers.
GeNeuro’s temelimab — also in development for patients with type 1 diabetes — is a monoclonal antibody designed to neutralize pHERV-W Env.
The researchers were aiming to find whether pHERV-W ENV is also implicated in nerve fiber injury in MS. They first found that, in chronic and acute brain lesions of five MS patients, pHERV-W ENV is located in myeloid cells — such as microglia or monocytes — containing the immune protein TLR4. These five patients were a 50-year-old woman with relapsing-remitting MS, another woman (age 63) with primary progressive MS, and three others (two men and one woman, ages 51 to 57) with secondary progressive MS.
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