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.
These investigators then found that pHERV-W ENV induces degeneration in microglial cells that are in direct contact with myelinated axons.
Data further showed that, in human and rat microglia, pHERV-W ENV increases cell proliferation, driving the release of proinflammatory molecules — including TNF-alpha, a mediator of myelin loss, lessens the production of neuroprotective factors such as IGF-1, and reduces myelin clearance. When stimulated by pHERV-W ENV proteins, microglia also shift to the M1 phenotype to set in place processes that damage nerve fibers.
“These observations suggest that in the MS brain, pHERV-W ENV may induce myeloid cells to cause damage of myelinated axons,” the scientists wrote.
“This study clearly shows that this pathogenic protein, via microglia, directly harms axons and leads to the neurodegeneration, as is observed in progressive MS,” Hervé Perron, PhD, GeNeuro’s chief scientific officer, said in a press release.
Its findings add to those of the CHANGE-MS Phase 2b trial (NCT02782858) in RRMS patients and its extension study, named ANGEL-MS (NCT03239860). ANGEL was ended early for reasons related to company operations, it was reported in March, but between these two trials, 154 RRMS patients were treated with temelimab intravenously for at least 96 weeks and their end-of-study analyses were the basis of results.
Those results found that temelimab treatment eased brain atrophy (shrinkage), preserved myelin, and slowed disease progression in these people. But CHANGE did not reach with significance its primary goal of lowering “the cumulative number of gadolinium-enhancing lesions seen on brain MRI scans after 6 mo (24 wk) of temelimab treatment,” the researchers wrote.
“That is why additional studies in a more appropriate population (i.e., nonactive progressive MS patients) at higher doses are currently in a planning stage,” they added.
Temelimab was well-tolerated in both studies.
“These data contribute further to our understanding of the pHERV-W Env neutralizing effects of temelimab, particularly with respect to the neuroprotective outcomes seen in our Phase 2b clinical studies,” Perron concluded.
Of note, one of the study authors is affiliated with GeNeuro.
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