Aicardi-Goutieres Syndrome

Rome Therapeutics and University of Michigan researchers validated their target in human skin cells from people with lupus. 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. 

Presentation at the American College of Rheumatology Convergence 2023 showcased first-ever data correlating LINE-1 expression and type 1 interferon response in skin of patients with lupus ROME’s first-in-class LINE-1 reverse transcriptase (RT) inhibitor led to reduction in inflammatory markers in both in vivo and in vitro models, demonstrating therapeutic potential in autoimmune diseases Data also demonstrate utility of skin-based UV photoprovocation as a translational model for future clinical studies 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 .

24-Week data show TPN-101 is the first treatment for PSP to reduce NfL levels, a key biomarker of neurodegeneration in tauopathies such as PSP and Alzheimer's disease TPN-101 also showed a reduction in IL-6 cytokine levels, a biomarker of neuroinflammation that is elevated in PSP patients and correlates with disease severity Once-daily oral dosing of TPN-101 was well-tolerated by patients with PSP Transposon to report data from three Phase 2 clinical studies of TPN-101 in four disorders, including PSP, amyotrophic lateral sclerosis, frontotemporal dementia, and Aicardi-Goutières Syndrome, in Q1 2024 SAN DIEGO, Nov. 14, 2023 /PRNewswire/ -- Transposon Therapeutics, a biotechnology company developing a platform of novel, orally administered therapies for the treatment of neurodegenerative and aging-related diseases, today announced its abstract of interim results from its Phase 2 study of TPN-101 for the treatment of progressive supranuclear palsy (PSP) has been accepted for poster presentation at the hybrid AD/PD™ 2024: 18th International Conference on Alzheimer's and Parkinson's Diseases. The meeting will take place online and in Lisbon, Portugal, from March 5-9, 2024. The poster presentation will highlight results from the study's predefined interim analysis, which examined the change from baseline to 24 weeks in biomarkers of neurodegeneration and neuroinflammation, including neurofilament light chain (NfL) and interleukin 6 (IL-6) levels in cerebrospinal fluid (CSF). In the treatment group receiving 400 mg of TPN-101 once daily for 24 weeks, TPN-101 showed an 18.4% reduction in NfL levels in CSF as compared to placebo. NfL is a biomarker of neurodegeneration that correlates with disease severity and progression in PSP. In the same 400 mg treatment group, TPN-101 also resulted in a 51.6% reduction in IL-6 levels in CSF as compared to placebo. IL-6 is a biomarker of neuroinflammation that is elevated in PSP patients and correlates with disease severity. Once-daily oral dosing of TPN-101 was well-tolerated at all dose levels. "No previously tested drug has shown an effect on NfL levels in patients with PSP, a progressive neurological disorder with no approved treatment options to stop or even slow progression of the disease," said Andrew Satlin, M.D., Chief Medical Officer at Transposon. "The lowering of CSF NfL levels seen in this interim analysis provides biomarker evidence of a treatment effect on neurodegeneration. We are excited about the potential of TPN-101 as a much-needed treatment option for patients with PSP. In addition, we believe these findings open the door to an entirely new therapeutic approach to treating Alzheimer's and other neurodegenerative diseases." "The Transposon team continues to make excellent progress against our key development milestones and corporate priorities, and we look forward to presenting these interim results from our PSP program at the AD/PD 2024 International Conference on Alzheimer's and Parkinson's Diseases," said Dennis Podlesak, Chairman and Chief Executive Officer of Transposon. "Beyond the promising reduction in NfL levels seen in our PSP study, we also look forward to reporting data from our three ongoing Phase 2 programs of TPN-101 in the first quarter of 2024 and, importantly, to expanding our development efforts for the compound into Alzheimer's disease and other neurodegenerative and autoimmune disorders." Transposon will present results from the interim analysis in a poster presentation (abstract #433) at AD/PD 2024 entitled: "A Phase 2a Study of TPN-101, a Nucleoside Reverse Transcriptase Inhibitor, in Patients with Progressive Supranuclear Palsy." For more information, please visit the AD/PD™ 2024 website. About the Phase 2 study in PSP The Phase 2 study in PSP is a multi-center, randomized, double-blind, placebo-controlled, parallel-group, 4-arm study with an open-label treatment phase in patients with PSP. Patients (N=42) were randomized to receive daily doses of 100 mg, 200 mg or 400 mg of TPN-101, or placebo. The study includes a 6-week screening period, a 24-week double-blind treatment period, a 24-week open label treatment period, and a follow-up visit 4 weeks post treatment. The predefined interim analysis was performed after all patients completed the 24-week double-blind portion of the study. The open-label extension of the study is ongoing. Further information on the study can be accessed at ClinicalTrials.gov. About TPN-101 TPN-101 specifically inhibits the LINE-1 reverse transcriptase that promotes LINE-1 replication. LINE-1 elements are a class of retrotransposable elements that in humans are uniquely capable of replicating and moving to new locations within the genome. When this process becomes dysregulated, LINE-1 reverse transcriptase drives overproduction of LINE-1 DNA, triggering innate immune responses that contribute to neurodegenerative, autoimmune and aging-related disease pathology. About PSP PSP is a rare and fatal tauopathy with no approved treatment options. PSP mainly affects people in their mid-to late-60s and is characterized by early postural instability and falls, vertical gaze palsy, akinesia, rigidity, pseudobulbar palsy, and frontal dysfunction with cognitive and behavioral changes. The mean survival for individuals with PSP is 6 to 7 years. About Transposon Transposon Therapeutics, Inc. is a clinical-stage biopharmaceutical company developing a platform of novel therapies for the treatment of neurodegenerative and aging-related diseases, including Alzheimer's disease. The company's lead clinical compound, TPN-101, is first-in-class to address LINE-1 reverse transcriptase for treating neurodegenerative and autoimmune diseases. Transposon will report data from three Phase 2 clinical studies of TPN-101 in four disorders, including progressive supranuclear palsy (PSP), amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and Aicardi-Goutières syndrome (AGS), in Q1 2024. The company also has a discovery platform supporting a deep pipeline of novel therapies to address additional indications. Contact: Rick Orr Transposon Therapeutics, Inc. (858) 535-4821 [email protected] SOURCE Transposon Therapeutics