Inhibiting LINE-1 retrotransposons therapeutically in disease

The LINE-1 retrotransposon is a virus-like genomic element that can activate in diseased cells. It has been implicated in cancer, autoimmunity, developmental disorders, infectious disease and neurodegeneration. LINE-1 can be inhibited by reverse transcriptase inhibitors, small molecules originally developed for HIV. The correlation between HIV and LINE-1 inhibition is ∼0.9 on a log scale, in spite of >450 Mya of evolutionary history since retroviruses diverged from retrotransposons. Suppression of HIV requires prevention of a completed 9.7 kb virus insertion into the genome in immune cells. However, every cell in the body already contains >100 copies of LINE-1 that can potentially activate. Even incomplete LINE-1 mediated insertions can cause damaging mutations and genome instability. Furthermore, partial HIV and LINE-1 products in the cytoplasm of cells can contribute to an inflammatory immune response. Preclinical studies have shown LINE-1 inhibitors slow the progression of otherwise unrelated diseases. LINE-1’s contribution to these diseases can potentially be quantified using single-nucleus whole-genome sequencing on diseased tissue, enabling prioritization of disease selection for therapeutic development. Furthermore, LINE-1’s ORF1p protein can be measured in the blood of individuals with certain cancers. LINE-1 inhibitors could therefore be extended to various diseases. Potentially used both as an anti-inflammatory and prophylactically to help preserve genome integrity. Reverse transcriptase inhibitors are available at low cost for HIV, and higher doses of some could be used to inhibit LINE-1. However, reverse transcriptase inhibitors do not prevent DNA cutting by LINE-1’s endonuclease. Novel inhibitors may therefore be required. This, combined with novel diagnostics opens up possibilities for inhibiting LINE-1 therapeutically in disease