More about MS and pathogenic HERV-W 

Multiple Sclerosis (MS) is an inflammatory, demyelinating disease of the central nervous system. It is generally assumed that MS is mediated by an autoimmune process. Episodes of acute focal inflammation in the central nervous system lead to demyelination which is followed by axonal damage and loss.

The median prevalence of MS in Europe is about 80 per 100 000 and varies according to the country, being more prevalent in Northern latitudes. In the US the prevalence of MS is approximately 149 per 100 000. The clinical course of MS varies considerably amongst patients, however most patients will eventually enter a stage of inexorable progression in neurological disability, termed “Progressive MS”. Three clinical forms of MS have been described: relapsing-remitting (RRMS), secondary progressive (SPMS) and primary progressive (PPMS). The most common presenting form is RRMS, accounting for approximately 85% of patients. RRMS is much more common in women than in men (approximately 3 : 1) and is characterized by sub-acute attacks of neurological dysfunction (termed “relapses”), followed by periods of stability or partial recovery (termed “remissions”). Most patients with RRMS will eventually enter a secondary, progressive form of the disease (SPMS), characterized by fewer and fewer relapses superimposed on slow, inexorable worsening. PPMS is less common, accounting for approximately 15% of patients at presentation, with no gender preference. PPMS is characterized by progressive worsening in neurological functioning from onset and few, if any relapses.

Figure 1 - Parallel drivers of MS Pathology from onset: Neuroinflammation and Neurodegeneration (axonal loss/brain atrophy); adapted from Compston et al. The Lancet 2002.

Currently, more than half a dozen disease modifying therapies (DMTs) are approved for marketing to treat MS and more than 20 are currently in clinical development. None of the currently-approved DMTs have been shown to stop disease progression but can be very effective in preventing CNS inflammation. Today, MS treatments can be divided into two basic categories: DMTs decrease the risk of relapses and the number of inflammatory lesions seen in brain MRI scans. However, as all DMTs modulate or suppress patient’s immune system, they can induce frequent and sometimes severe adverse drug reactions. Symptomatic agents reduce specific symptoms associated with MS, such as spasticity, but they do not interact with the disease mechanism and do not affect disease progression. In addition, most of the current and in-development treatments are indicated for the relapsing-remitting form of MS, with few therapeutic options in development for the progressive forms of MS.

Figure 2 - Main drivers of multiple sclerosis

The greatest unmet medical need for multiple sclerosis is the development of treatments incorporating neuroprotection and remyelination to treat and ultimately prevent the disabling, progressive forms of the disease.

The etiology of MS is uncertain but evidence suggests that genetic and environmental factors act in combination to result in MS.  Several studies have demonstrated the potential role of the pHERV-W  endogenous retrovirus in MS.

pHERV-W was first isolated from cells of MS patients. pHERV-W is normally latent in the genome of individuals. When activated by certain co-factors such as the common viruses, e.g. Herpes Simplex virus 1 or Epstein Barr virus, it expresses pHERV-W Env.

 Figure 3 - Immunohistochemistry staining of pHERV-W Env in brain sections isolated from MS patients post-mortem.

pHERV-W Env expression is mainly restricted to macrophages/monocytes and microglia. Immunohistochemistry experiments in brain sections of post-mortem MS patients applying various monoclonal antibodies (mAbs) directed against different epitopes of pHERV-W Env reveal the presence of pHERV-W Env in all samples thus far analyzed (see Figure 3). Its association with areas of active demyelination from active to chronic brain lesions, with fairly intense expression until the death of the patient suggests an involvement in the long-term pathogenic progression of the disease.

pHERV-W Env appears to be a major triggering and aggravating factor in the development and progression of MS, as shown in numerous scientific papers published by GeNeuro’s team and other leading academic centres.

Figure 4 - pHERV-W Env acts on two key cell types of MS disease progression:

Microglia and Oligodendrocyte Precursor Cells (OPC) 

By neutralizing pHERV-W Env, GeNeuro’s lead product temelimab seeks to stop microglial-fueled neurodegeneration as well as allow OPC-mediated remyelination. This is in line with the clinical results of GeNeuro’s CHANGE-MS Phase IIb trial.

Figure 5: Findings in CHANGE-MS are supported by GeNeuro’s preclinical knowledge