A new approach by targeting pathogenic products, encoded by human endogenous retroviruses

GeNeuro is developing a new approach to the treatment of diseases associated with human endogenous retrovirus (HERV) expression.

The sequencing of the human genome has revealed that nearly one-half of the genome is composed of transposable elements (TEs), the discovery of which led to the Nobel Prize being awarded to Barbara McClintock in 1983. TEs are important in eukaryotic genomic function and evolution. TEs include DNA transposons and retrotransposons, which include human endogenous retroviruses (HERVs). HERVs alone account for up to 8% of the human genome. HERVs are believed to have originated from retroviral infections of germline cells, resulting in viable offspring carrying retrovirus DNA insertions (termed “proviruses”), which have been passed down to the genomes of modern humans from our primate ancestors.

Despite the accumulation of mutations, stop codons and epigenetic mechanisms to silence their genetic expression, HERVs are still contributing to the human transcriptome, and a growing number of findings suggest that their expression products may, in addition to their roles in normal physiology, play pathogenic roles in various diseases.

Among the HERV-encoded proteins, the envelope proteins (Env) are currently highly investigated for their pathogenic properties, which could be contributing to several disorders with complex, and as yet unidentified etiologies, particularly in the contexts of neurodegeneration, autoimmunity and cancer. In some instances, envelope proteins are even considered to be the causal factor of disease. Amongst them, the pathogenic HERV-W Env (pHERV-W Env) is perhaps the best studied.

In the 1990’s a pathogenic member of the HERV-W family, initially referred to the multiple sclerosis associated retrovirus (MSRV), was discovered in cell cultures isolated from leptomeningeal cells taken from the cerebrospinal fluid (CSF) of patients affected with multiple sclerosis. As described above, HERVs are normally genetically and/or epigenetically repressed in healthy individuals. However de-repression and transcription (i.e. ”transactivation”) of pHERV-W-encoded gene products, including the env protein, was demonstrated in these cells when exposed to exogenous viral infections such as Epstein Barr Virus (EBV), as well as other viruses of the herpes family, which have been epidemiologically associated with MS. Over the next 2 decades, research has begun to clarify the pathophysiological mechanisms of pHERV-W in MS. Further evidence includes demonstration of pHERV-W Env in active MS lesions based on post-mortem neuropathological studies and preferential expression of pHERV-W genomic transcripts in peripheral blood mononuclear cells (PBMCs) of patients with MS versus normal controls. In CSF, expression of pHERV-W transcripts not only correlate with the diagnosis of MS but also with disease severity and the risk of progression.

As exemplified by pHERV-W Env appearing to be a major triggering and aggravating factor in the development and progression of MS, other HERVs outside of the W-family may provide a missing link in understanding certain, complex neurodegenerative and autoimmune diseases for which the etiologies are currently unknown. Depending on environmental co-factors and target organs, pathogenic HERV-encoded products could, in general, not only be involved in multiple sclerosis, but other diseases with high unmet medical need, such as Type 1 diabetes, chronic inflammatory demyelinating polyneuropathy (CIDP), inflammatory psychoses and certain forms of amyotrophic lateral sclerosis (ALS).