Rome Therapeutics' 'dark genome' therapy shows early efficacy against autoimmune disease in mice

Preclinical tests of Rome Therapeutics' first-of-its-kind drug show that it’s effective in reducing a type of inflammation believed to promote autoimmune diseases like lupus. 

In a poster (PDF) published online Nov. 16 and presented Nov. 12 at the American College of Rheumatology’s 2023 Convergence conference, the company shared that RPT-A was effective in reducing autoantibodies in mouse models of autoimmune disease. They also presented data from human studies demonstrating that LINE-1 RT was a viable drug target. 

“These data are the first to validate LINE-1 RT as a novel therapeutic target for potential therapeutic intervention across a wide range of autoimmune diseases,” Rome CEO Rosana Kapeller, M.D., Ph.D., said in a press release, adding that the data marked a “significant milestone” for the company.

Rome’s focus is on building therapies that manipulate the “dark genome." Once misleadingly termed “junk DNA,” it makes up more than 98% of the roughly three billion letters of DNA that don’t code for proteins. Instead, elements of the dark genome—which is primarily made up of repeated sequences of base pairs, often called “repeats” for short—regulate where, how and when genes are expressed. 

RPT-A is designed to control autoimmune disease by inhibiting a specific type of dark genome repeat called Long Interspersed Element-1, or LINE-1, a retrotransposon, or “jumping gene," that makes copies of itself so it can move around and control gene expression in different parts of the genome. As Rome pointed out in the ACR poster, there is evidence that LINE-1 might trigger autoimmune diseases by activating peptides called type I interferons, inflammatory cytokines that are part of the normal innate immune response but are elevated in people with conditions like lupus.

To further expand on LINE-1’s role in autoimmune disease and justify it as a therapeutic target, Rome worked with researchers at the University of Michigan to see if it was expressed in the skin of patients with systemic lupus erythematosus, or SLE, the most common type of lupus. They took skin biopsies from healthy people and people with lupus and exposed them to UV light. In lupus patients, UV light causes an immune reaction that leaves its mark as a dry, itchy rash, a sign of inflammation. Their findings showed that LINE-1 was expressed to a greater degree in the skin of people with lupus than in healthy people after UV exposure, as were markers of type I interferon production. 

After running additional experiments on skin cells to see how knocking down the LINE-1 gene changed the inflammatory response to UV light, they turned to testing RPT-A in mouse models of Aicardi-Goutières syndrome, a genetic condition with characteristics of autoimmune disease. They found that the drug reduced autoantibodies associated with autoimmune disease as well as heart and kidney inflammation. Experiments on human cells showed that LINE-1 stimulation inhibited type I interferon production.

“Inhibition of LINE-1 reverse transcriptase holds promise as a novel therapy for diseases in which type I [interferons] drive disease,” the researchers concluded in their paper. 

Rome’s drug is currently undergoing investigational new drug-enabling studies, according to the company’s website.