ROME Therapeutics Presents First Data to Validate LINE-1 RT as a Novel Target in Autoimmune Diseases and the Therapeutic Potential of its First-in-Class LINE-1 RT Inhibitors

BOSTON--(BUSINESS WIRE)-- ROME Therapeutics, a biotechnology company harnessing the power of the dark genome to develop breakthrough medicines for serious diseases, announced new data validating the reverse transcriptase (RT) of LINE-1, an abundant repeat element in the dark genome, as a novel target for drug discovery in autoimmune diseases, including lupus. Data also demonstrated the therapeutic potential of the company’s first-in-class LINE-1 RT inhibitors to stop disease-driving inflammation. The data were unveiled in a presentation at the American College of Rheumatology (ACR) Convergence 2023, available for viewing here.

ROME is focused on translating its unique understanding of virus-like repeat elements within the dark genome to advance therapeutics for patients with significant unmet needs. The company’s lead program targets LINE-1 RT, which reverse transcribes RNA into DNA in the cytoplasm of a cell and triggers an innate immune response via nucleic acid sensors, leading to activation of type 1 interferon, an immune-stimulating cytokine that drives autoimmune disease pathology.

The data presented at ACR Convergence and generated in collaboration with Michelle Kahlenberg, M.D., Ph.D., Giles Boles and Dorothy Mulkey Research Professor of Rheumatology at the University of Michigan, for the first time demonstrate the association between LINE-1 and interferon response in the skin of lupus patients. Using a skin-based UV photoprovocation model, researchers showed that LINE-1 is expressed in the skin of individuals with the autoimmune disease systemic lupus erythematosus (SLE) and that LINE-1’s expression corresponds to increased activation of the type 1 interferon pathway. Neither LINE-1 nor interferon markers were observed in the skin of healthy volunteers. Exposure to UV stimulation dramatically increased LINE-1 and markers of the interferon pathway in the skin of SLE patients, and to a lesser degree, skin from healthy volunteers. Collectively, these results validate the correlation between LINE-1 expression and the type 1 interferon cascade, and demonstrate the relevance of blocking LINE-1 activity as a novel approach to treating lupus. These data also demonstrate the utility of skin-based UV photoprovocation as a translational model to measure biological activity and therapeutic impact of ROME’s LINE-1 RT inhibitors in future clinical studies.

Additionally, the poster highlighted the first preclinical data demonstrating the therapeutic potential of ROME’s first-in-class inhibitors of LINE-1 RT. In a mouse model of Aicardi-Goutières syndrome (AGS), a rare genetic disease with features characteristic of autoimmune diseases, treatment with one of ROME’s LINE-1 RT inhibitors significantly reduced autoantibodies against double-stranded DNA, a hallmark of autoimmune diseases like lupus, as well as inflammation in the heart and kidney. In vitro data in human keratinocytes and cellular models of AGS showed similar results, inhibiting the downstream interferon pathway that results from LINE-1 stimulation.

“In my clinical practice treating people with lupus and other autoimmune diseases, I see daily the need for new approaches to treating these complex conditions,” said Dr. Kahlenberg. “I’m excited that this research collaboration has shed light on the importance of LINE-1 activity as a driver of the downstream inflammation that is a key feature of autoimmune disease, and the potential of blocking this activity with inhibitors of reverse transcriptase, opening up the possibility of novel therapeutic approaches that could improve patients’ health and quality of life. I look forward to seeing the discovery and development of therapeutics against LINE-1, as our understanding of this novel target and its biology concomitantly grows and evolves.”

“As a leader in the emerging dark genome space, ROME is fully committed to advancing scientific understanding of the role dark genome-related biology plays in disease pathology. To that end, we’re very excited to share the robust evidence we’ve generated linking LINE-1 expression and type 1 interferon response. These data are the first to validate LINE-1 RT as a novel target for potential therapeutic intervention across a wide range of autoimmune diseases,” said Rosana Kapeller, M.D., Ph.D., President, CEO and Co-founder of ROME. “We’re also pleased to share the first in vivo and in vitro data validating the therapeutic effect of our first-in-class LINE-1 RT inhibitors in the autoimmune disease setting. Collectively, these data mark a significant milestone for our company as we continue to advance our LINE-1-focused research activities, including our lead LINE-1 RT inhibitor for lupus.”

About LINE-1

Long Interspersed Nuclear Elements, or LINEs, are a ubiquitous family of transposable, virus-like elements embedded in the dark genome at the DNA level. A LINE can make new copies of itself through a reverse transcriptase mechanism. LINE-1 encodes several proteins, including a protein called ORF2, which contains both a reverse transcriptase (RT) domain that can reverse transcribe the LINE-1 RNA, making a new DNA copy, and an endonuclease domain, that can insert the DNA copy into a new genomic location. Activity of LINE-1 RT in the cytoplasm can result in cytosolic RNA-DNA hybrids triggering an innate immune response that can drive autoimmune disease pathology. Through rational structure-based drug design, ROME has designed novel, selective, and potent inhibitors of LINE-1 RT to block this immune response.

About ROME

ROME Therapeutics is developing novel therapies for a range of serious diseases, including autoimmune disease, cancer, and neurodegeneration, by illuminating the role of the dark genome — the vast genomic expanse beyond the traditional genes, which includes virus-like repetitive elements and non-coding sequences — in human health and disease. Leveraging the company’s unprecedented data sciences platform, ROME has built a deep pipeline of therapies targeting the dark genome. To lead this exploration, ROME has assembled a team of world-class leaders in drug discovery and development across immunology, oncology, chemistry, and machine learning. ROME is based in Boston, Mass. For more information, please visit www.rometx.com.

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