GeNeuro To Tackle Long COVID By Targeting Ancestor Viral Gene Activation
Will Assess Its HERVs MAb Temelimab in Covid-19 Patients
Executive Summary
Switzerland’s GeNeuro will study whether its monoclonal antibody temelimab can prevent long-COVID, after data for the first time linked activation of human endogenous retroviruses (HERVs) to the condition and its associated neurological symptoms.
Swiss biotech GeNeuro SA is to test its investigational lead asset temelimab in COVID-19 patients, encouraged by new data suggesting that infection could activate the pathogenic envelope protein of the human endogenous retrovirus W (HERV-W ENV).
It seems there is a genetic and/or epigenetic susceptibility to severe COVID-19 tied to activation of the pro-inflammatory HERV-W ENV protein in blood lymphoid cells, a finding that could help in understanding how SARS-CoV-2 infection may lead to severe disease in some patients. The findings, combined with the known pro-inflammatory properties of the HERV-W ENV protein, may shed a new light on the development of severe forms of COVID-19, and may also offer an unforeseen opportunity to stop this evolution through a novel therapeutic approach, researchers say.
About 8% of the human genome is composed of sequences with viral origin, namely HERVs, which are relics of ancient infections that affected the primates' germ line along the last 100 million of years.
Although HERVs usually lie dormant, environmental factors – like other viruses, drugs or mutations – can awaken them and their dangerous consequences. Strong evidence links HERVs to multiple sclerosis, in which the body launches an immune response against its own nervous system.
Although this link between viral infection and HERV activation in specific diseases has already been well documented, until now, HERV expression had been observed in limited amounts and mainly found in an affected organ, mainly in the brain in neurodegenerative disorders.
The discovery of HERV-W ENV circulating in the blood of COVID-19 patients potentially opens a new dimension to the disease and efforts to develop treatments to neutralize the pathogenic effects of HERVs.
The research, conducted by a team at University of Rome Tor Vergata in collaboration with the International Center for Research in Infectious Diseases in Lyon, France and GeNeuro, was published 15 April in Lancet EBiomedicine in the paper Evidence of the pathogenic HERV-W envelope expression in T lymphocytes in association with the respiratory outcome of COVID-19 patients
It reported high levels of endogenous retrovirus in the blood of hospitalized COVID-19 patients. Preliminary findings also show that when human peripheral blood mononuclear cells from healthy donors were cultured and exposed to SARS-CoV-2, some 20% of donors responded by expressing HERV-W ENV in lymphocytes, cells in which the virus does not replicate. This expression was triggered specifically by the Spike protein of SARS-CoV-2, independently from cytokine release, the researchers said.
“Our findings on HERV-W ENV in the blood of hospitalized COVID-19 patients are truly novel as this pro-inflammatory protein is usually found in specific disease situations, mostly in the brain, but has never before been observed circulating in the body at high levels and, in particular, was never seen expressed in T-lymphocytes,” said Claudia Matteucci, who led the research team at University of Rome Tor Vergata.
GeNeuro’s chief scientific officer Hervé Perron who has been working on HERVs for over 30 years said the presence of HERV-W ENV circulating in the blood of COVID-19 patients may have a double effect. “In the short-term, when activated in susceptible individuals, HERV-W ENV can act as an accelerant to the innate immune response, fueling complications and leading to the need for ventilation. But even after the primary infection is over, if HERV-W ENV has reached a self-fueling expression level, it may cause persistent damage to endothelial cells in blood vessels and also to cells from the peripheral and central nervous system, which could explain many of the long-haul neurological symptoms experienced by patients long after SARS-CoV-2 infection.”
In multiple sclerosis, where the HERV-W ENV protein is consistently found in patients’ brains it contributes to neurodegeneration through the activation of microglia and the inhibition of the brain’s remyelination capacity.
GeNeuro was founded in 2006 as a spin-off of Institut Mérieux to leverage HERV biology into novel treatments by neutralizing pathogenic HERV proteins. Its CEO, Jesús Martin-Garcia, told Scrip that the association between HERV-W ENV expression and inflammatory and immune dysfunction in COVID-19 opens the way for deeper investigation of its role as a trigger of detrimental immune response and potential target for therapy.
The biotech’s most advanced drug candidate, temelimab (formerly GNbAC1), an immunoglobulin G4 that targets HERV-W-ENV, has shown promising results in Phase II trials against multiple sclerosis, and is currently in a trial against disability progression at the Karolinska Institutet’s Academic Specialist Center in Stockholm, Sweden, with topline data expected in Q1 2022.
Martin-Garcia said GeNeuro would launch clinical trials with temelimab this summer in university centers in Germany, Italy and France in early-stage patients, the purpose being to prevent severe COVID-19 symptoms.
“This latest HERV data in COVID patients is quite intriguing because SARS-CoV-2 does not replicate in lymphocytes. It appears that COVID is a HERV-mediated disease, a disease where HERVs play a role. So neutralizing HERV-W ENV could be a new lever to fight SARS-CoV-2,” Martin-Garcia said.
Martin-Garcia said neutralizing HERV-W ENV is an attractive strategy against neurodegeneration, which is the key market opportunity for the next decade in MS.
“This doesn’t change our strategy – we’re not becoming a COVID company. We remain committed to leveraging HERV biology to bring solutions to large unmet medical needs. MS is at the core of that mission and we look forward to presenting our Phase II clinical results in the first quarter of 2022.”