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Abstract Number: 0633

Novel LINE-1 Reverse Transcriptase Inhibitors Can Suppress Type I Interferon Responses and Are Promising Therapeutics for Lupus

Wenyan Miao1, Digna de Bruin2, Cedric Arisdakessian1, Jannik Rousel2, Jared Steranka1, Matthijs Moerland2, Eric Jacobson1, Mehrnaz Gharaee-Kermani3, Liyang Diao1, Craig Dobry3, Nafeeza Hafeez1, Brian Desrosiers1, J. Michelle Kahlenberg3, Heike Keilhack1, Robert Rissmann2, Keith M Wilcoxen1 and Tessa Niemeyer-van der Kolk2, 1Rome Therapeutics, Boston, MA, 2Centre for Human Drug Research, Leiden, Netherlands, 3University of Michigan, Ann Arbor, MI

Meeting: ACR Convergence 2024

Keywords: Cutaneous, Imaging, interferon, skin, Systemic lupus erythematosus (SLE)

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Session Information

Date: Saturday, November 16, 2024

Title: SLE – Diagnosis, Manifestations, & Outcomes Poster I

Session Type: Poster Session A

Session Time: 10:30AM-12:30PM

Background/Purpose: Long Interspersed Element-1 (LINE-1) retrotransposon encodes for two proteins, ORF1p and ORF2p. ORF1p is a chaperone protein while ORF2p contains reverse transcriptase (RT) and endonuclease activities. LINE-1 RT can reverse transcribe LINE-1 and other RNAs into RNA:DNA hybrids and double stranded DNA. These nucleic acid products can trigger the cGAS/STING pathway to induce Type I interferon (IFN) response. LINE-1 is quiescent in healthy tissues but can be induced under pathological conditions and cellular stress. We have previously shown that higher levels of LINE-1 protein and RNA are present in SLE skin, and that a LINE-1 RT inhibitor (RTI) can block cGAS/STING-mediated IFN response. In this study we investigated the ability of LINE-1 RTIs to suppress Type I IFN responses in human skin explants and in a murine interferonopathy model. In addition, we have developed a UV-B skin challenge model in healthy volunteers to use in Phase 1 clinical studies.

Methods: LINE-1 RTIs, RPT-A and RPT-B, were characterized by using a LINE-1 RT polymerase biochemical assay and various cellular assays. We assessed the impact of ex vivo treatment with the inhibitors on UV-induced IFN responses in skin explants. We also studied the efficacy of these inhibitors in an interferonopathy mouse model (TREX1 knockout mice). Finally, we conducted a clinical study in which the skin of 10 healthy subjects was irradiated with UV-B on two different study days, two weeks, apart to investigate UV-induced skin inflammation and IFN response. The inflammatory reaction was monitored using non-invasive imaging and skin biopsies were collected and examined for interferon-stimulated genes (ISG) expression.

Results: RPT-A and RPT-B potently inhibited the polymerase activity of LINE-1 RT, as well as cellular LINE-1 retrotransposition, DAC-induced interferon response in TREX1-deficient THP-1 cells, UV-induced pTBK1 in human HaCaT keratinocytes, and UV-induced ISG in primary keratinocytes derived from healthy and lupus skin. Ex vivo treatment of skin explants from healthy subjects with the inhibitors suppressed UV-induced sunburned cells, oxidized DNA, and ISG expression. Five to six-week-old TREX1 knockout mice dosed orally with RPT-A and RPT-B showed reduced serum anti-dsDNA antibodies, heart and kidney immune infiltrates, and myocardial ISGs. In the healthy volunteer UV challenge study, UV-B increased erythema and perfusion as assessed by imaging which reached peak induction by 6 hours post UV and remained elevated 24 hours post UV. The level of induction is consistent between subjects and between the two periods of UV provocation. RNA-seq data of the skin biopsies revealed ISG induction at 24 hours post UV in both periods.

Conclusion: Inhibition of LINE-1 RT activity results in suppression of UV-induced IFN response in keratinocytes and skin explants, and decreased disease activity in a murine interferonopathy model. Our clinical study demonstrated the feasibility of using UV provocation in healthy volunteers as proof-of-mechanism clinical study for LINE-1 RT inhibitors. Together, inhibition of LINE-1 reverse transcriptase holds promise as a novel therapy for Type I interferon driven diseases.


Disclosures: W. Miao: None; D. de Bruin: None; C. Arisdakessian: None; J. Rousel: None; J. Steranka: None; M. Moerland: None; E. Jacobson: None; M. Gharaee-Kermani: None; L. Diao: None; C. Dobry: None; N. Hafeez: None; B. Desrosiers: None; J. Kahlenberg: Amgen, 12, coauthor on publication, AstraZeneca, 2, Bristol-Myers Squibb(BMS), 2, 5, Eli Lilly, 2, Gilead, 2, GlaxoSmithKlein(GSK), 2, Janssen, 5; H. Keilhack: None; R. Rissmann: None; K. M Wilcoxen: None; T. Niemeyer-van der Kolk: None.

To cite this abstract in AMA style:

Miao W, de Bruin D, Arisdakessian C, Rousel J, Steranka J, Moerland M, Jacobson E, Gharaee-Kermani M, Diao L, Dobry C, Hafeez N, Desrosiers B, Kahlenberg J, Keilhack H, Rissmann R, M Wilcoxen K, Niemeyer-van der Kolk T. Novel LINE-1 Reverse Transcriptase Inhibitors Can Suppress Type I Interferon Responses and Are Promising Therapeutics for Lupus [abstract]. Arthritis Rheumatol. 2024; 76 (suppl 9). https://acrabstracts.org/abstract/novel-line-1-reverse-transcriptase-inhibitors-can-suppress-type-i-interferon-responses-and-are-promising-therapeutics-for-lupus/. Accessed .
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