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Drug hunters are finding that ancient virus-like artifacts in the human genome could offer new avenues to treat neurodegeneration, cancer, autoimmunity and even aging with antibodies, vaccines and antiretroviral agents. A new wave of therapies is taking aim at virus-like elements spread throughout the human genome. These genomic parasites, which have accumulated over the course of human evolution, are embedded in the vast expanse of DNA sequences that dwell in the spaces between our genes — what scientists call the ‘dark genome’. Although they were largely ignored in the past, growing scientific evidence indicates that these normally dormant elements — including retroviruses, transposons and other repetitive sequences — can reactivate, triggering inflammation, cancer and other disease-related cellular damage.
Several companies have recognized this reactivation as an untapped clinical opportunity and are developing therapeutics to stifle these ancient interlopers. For example, Transposon Therapeutics’ lead drug candidate, TPN-01, was originally devised as an antiretroviral drug to block proliferation of HIV-1, but also appears to be a potent inhibitor of a dark genome-dwelling transposon known as LINE-1 (long interspersed nuclear element-1). This February, Transposon Therapeutics announced promising results from a phase 2 trial testing TPN-01 as a treatment for the neurodegenerative disorder progressive supranuclear palsy (PSP). Venture investors and pharma are paying attention. In September 2023, dark genome startup Rome Therapeutics reported $77 million in series B funding from major players including Sanofi, Bristol Myers Squibb and Johnson & Johnson — bringing their total take for this round to $149 million. Many startups initially faced an uphill battle persuading investors of the clinical opportunities in the dark genome. “They’re tainted with the assumption of non-functionality and non-importance,” says Joseph Dukes, CSO at Oxford, UK-based Enara Bio, a company engaged in scanning the dark genome for antigens that may offer fruitful targets for cancer immunotherapy. Rosana Kapeller, CEO and co-founder of Rome Therapeutics, recalls being greeted with skepticism the first time she presented the company’s strategy at the J.P. Morgan Healthcare Conference in 2020. “People looked at me and said, ‘You’re nuts’,” she recalls.
The skepticism was understandable given that, until relatively recently, drug discovery has nearly exclusively focused on the exome: the 2% of the genome that codes for protein. But upwards of half the human genome consists of repetitive dark genome elements that have accumulated throughout evolution. For example, LINE-1 has a history dating back over 100 million years, and Kapeller estimates that this element composes roughly 20% of the genome. Most of these sequences are defunct fragments, but the roughly 150 intact LINE-1 sequences can potentially proliferate via a copy-and-paste mechanism driven in part by the LINE-1-encoded reverse transcriptase (RT) enzyme. Human endogenous retroviruses (HERVs) — which retain similar protein-coding genes to those seen in retroviruses like HIV, but lack the ability to produce replicating particles — are another important target. Both LINE-1 and HERV sequences are normally maintained in a quiescent state via DNA methylation, but events that lead to demethylation can cause these stowaways to ‘wake up’, potentially triggering a powerful immune response or other pathological outcomes....
