Monday, 15 September 2014

ECTRIMS 2014: HERVs are officially a therapeutic target in MS

Can we reduce human endogenous retroviruses or HERVs with a treatment? #MSBlog #MSResearch

"Just arrived back from Boston; exhausted physically, mentally and no doubt more to come with jet-lag. One of the highlights for me at ECTRIMS was the interest in human endogenous retroviruses (HERV) and MS. The following is some interesting preliminary results from the clinical study of a monoclonal antibody targeting the envelope protein of a HERV associated with MS. What it shows is that this antibody decreases expression of this virus and the protein. Hopefully these effects will be associated with a reduction in MS disease-activity. This is what we are trying to achieve in our INSPIRE study using a drug, raltegravir, that targets HERV biology. We will also be doing biomarker studies to see if we down-regulate peripheral HERV expression. Please remember HERV transactivation, or expression in MS, may simply be an epiphenomenon, of inflammation. This is why it is so important to  have to see if reduced expression of HERVs is associated with a therapeutic effect."


Background: GNbAC1 is an IgG4 humanized monoclonal antibody targeting and neutralizing pathogenic effects of MSRV-Env, a potent pro-inflammatory protein that also blocks oligodendrocyte precursor cell differentiation. This therapeutic target is an endogenous retroviral envelope from HERV-W family, which is abundantly expressed in microglia within active MS lesions and at the rim of chronic progressive plaques. HERV-W gag-encoded capsid protein is co-detected in MS lesions, which indicates HERV-W expression beyond the env-encoded pathogenic target.

Objectives: Follow-up mRNA expression in circulating blood cells of MS patients treated with GNbAC1 over the first six months of Phase IIa study with quantitative PCR targeting two different HERV-W genes, env and pol.

Methods: Peripheral blood mononuclear cells (PBMC) of patients collected during the first 6 months of Phase IIa (ClinicalTrials.gov Identifier: NCT01639300) were assessed by real time quantitative polymerase chain reaction (RT-qPCR). Expression levels of messenger RNA (mRNA) were assessed by different primers/probe sets specific for retroviral env and pol HERV-W genes.

Results: At inclusion, no difference in HERV-W transcript levels was observed between patients being enrolled in both cohorts (2 and 6mg/kg) and between recruiting centres. Nonetheless, the different qPCR protocols showed the highest HERV-W mRNA levels in Primary Progressive MS (PPMS) patients. Despite low numbers, statistically significant correlations were found between HERV-W env and pol mRNA levels and disease duration and/or progression index.
A decrease of all HERV-W mRNA levels was observed at the 6th GNbAC1 administration, when compared to basal values at inclusion in both cohorts. Statistical distribution of values measured before the first, third and sixth GNbAC1 injection in all patients showed unexpected decrease for both env and pol mRNA.

Conclusions: Specifically binding to HERV-W envelope protein and neutralizing its pathogenic activity, GNbAC1 is not expected to impact HERV-W gene expression. A significant decrease of mRNAs encoding retroviral proteins from different HERV-W structural genes therefore appears unique for an anti-envelope antibody and evidences an effect on HERV-W expression itself. 

This study showed:
i) a global anti-retroviral effect on HERV-W expression over six months of GNbAC1 treatment,
ii) evidence, beyond MSRV-Env endogenous protein itself, of an association between HERV-W expression and MS and
iii) PCR assays for potential companion diagnostic tests.

5 comments:

  1. The HERV-W expression is increased in microglia in active MS lesions and at periphery of chronic lesions. The study measured the mRNA levels in PBMCs after Ab treatment. Does this translate to microglial expression of HERV-W in the CNS?

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    1. http://www.ncbi.nlm.nih.gov/pubmed/?term=25002752 paper differentiates infiltrating monocytes from resident microglia and their roles in demyelination. Is there any evidence that infiltrating monocytes in MS patients are expressing EBV?

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  2. how does this study mean they are 'officially' a therapeutic target?

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  3. This is really an important research ProfG...
    Research begins to target the root cause of MS.
    But am I wrong or they have also elsewhere reported disease stability in trial partecipants?

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  4. Prof G,

    Glad to hear you got back safely. Did you allow Prof Mouse to travel with you in Business Class? He appeared to earn his corn while in the US. I'm glad I didn't experience a relapse last week - the great and the good of the UK MS world were all in Boston - Coles, Thompson, Chattaway, Giovannoni.... It would be good to year your view on the top 5 stories / research from the conference. I didn't see anything on the B cell depleting therapies. Will team G present the Charcot project results at next year's Ectrims conference?

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