A CRISPR-based approach to targeting a pathogenic TLR7 gene variant in systemic lupus erythematosus
DOI:
https://doi.org/10.58445/rars.2347Keywords:
lupus, Systemic Lupus ErythematosusAbstract
Systemic lupus erythematosus (SLE) is an autoimmune disease where the body's immune system becomes highly sensitive to non-pathogenic ssRNA, triggering an immune attack on healthy tissue. This incites inflammation, tissue damage, and life-long, adverse side effects. Research has linked over 50 genes to SLE, including the TLR7 gene, which is often overexpressed in individuals with SLE. Recently, a pathogenic variant of the TLR7 gene, known as TLR7-Y264H was demonstrated to oversensitize the toll-like receptors in the cell, resulting in the symptoms of SLE. There is a significant gap in research for SLE treatments, as current options often fail to provide long-term disease control with minimal toxicity. Therefore, this study explores a CRISPR-based approach to rectify this pathogenic variant of TLR7. In light of recent research highlighting the role of TLR7-Y264H mutation’s overexpression in SLE patients, this study investigates whether a CRISPR-based therapeutic approach can effectively dampen SLE symptoms.
References
Tian J, Zhang D, Yao X, Huang Y, Lu Q. Global epidemiology of systemic lupus erythematosus: a comprehensive systematic analysis and modelling study. Ann Rheum Dis 2023;82(3):351–6.
Ghodke-Puranik Y, Olferiev M, Crow MK. Systemic lupus erythematosus genetics: insights into pathogenesis and implications for therapy. Nat Rev Rheumatol 2024;20(10):635–48.
Guga S, Wang Y, Graham DC, Vyse TJ. A review of genetic risk in systemic lupus erythematosus. Expert Rev Clin Immunol 2023;19(10):1247–58.
Demkova K, Morris DL, Vyse TJ. Genetics of SLE: does this explain susceptibility and severity across racial groups? Rheumatol (Oxf, Engl) 2022;62(Suppl 1):i15–21.
Slight-Webb S, Thomas K, Smith M, Wagner CA, Macwana S, Bylinska A, et al. Ancestry-based differences in the immune phenotype are associated with lupus activity. JCI Insight 2023;8(16):e169584.
Tsokos GC. Systemic Lupus Erythematosus. N Engl J Med 2011;365(22):2110–21.
Durcan L, O’Dwyer T, Petri M. Management strategies and future directions for systemic lupus erythematosus in adults. Lancet 2019;393(10188):2332–43.
Lazar S, Kahlenberg JM. Systemic Lupus Erythematosus: New Diagnostic and Therapeutic Approaches. Annu Rev Med 2022;74(1):339–52.
Katarzyna PB, Wiktor S, Ewa D, Piotr L. Current treatment of systemic lupus erythematosus: a clinician’s perspective. Rheumatol Int 2023;43(8):1395–407.
Adli M. The CRISPR tool kit for genome editing and beyond. Nat Commun 2018;9(1):1911.
Knott GJ, Doudna JA. CRISPR-Cas guides the future of genetic engineering. Science 2018;361(6405):866–9.
Komor AC, Kim YB, Packer MS, Zuris JA, Liu DR. Programmable editing of a target base in genomic DNA without double-stranded DNA cleavage. Nature 2016;533(7603):420–4.
Gaudelli NM, Komor AC, Rees HA, Packer MS, Badran AH, Bryson DI, et al. Programmable base editing of A•T to G•C in genomic DNA without DNA cleavage. Nature 2017;551(7681):464–71.
Anzalone AV, Randolph PB, Davis JR, Sousa AA, Koblan LW, Levy JM, et al. Search-and-replace genome editing without double-strand breaks or donor DNA. Nature 2019;576(7785):149–57.
Ghodke-Puranik Y, Olferiev M, Crow MK. Systemic lupus erythematosus genetics: insights into pathogenesis and implications for therapy. Nat Rev Rheumatol 2024;20(10):635–48.
Guga S, Wang Y, Graham DC, Vyse TJ. A review of genetic risk in systemic lupus erythematosus. Expert Rev Clin Immunol 2023;19(10):1247–58.
Vinuesa CG, Shen N, Ware T. Genetics of SLE: mechanistic insights from monogenic disease and disease-associated variants. Nat Rev Nephrol 2023;19(9):558–72.
Wang FQ, Dang X, Yang W. Transcriptomic studies unravel the molecular and cellular complexity of systemic lupus erythematosus: A review. Clin Immunol 2024;268:110367.
Klonowska-Szymczyk A, Wolska A, Robak T, Cebula-Obrzut B, Smolewski P, Robak E. Expression of Toll‐Like Receptors 3, 7, and 9 in Peripheral Blood Mononuclear Cells from Patients with Systemic Lupus Erythematosus. Mediat Inflamm 2014;2014(1):381418.
Wang T, Marken J, Chen J, Tran VB, Li QZ, Li M, et al. High TLR7 Expression Drives the Expansion of CD19+CD24hiCD38hi Transitional B Cells and Autoantibody Production in SLE Patients. Front Immunol 2019;10:1243.
Fletcher L. Back to Basics – Base & Prime Editing [Internet]. 2024;Available from: https://frontlinegenomics.com/back-to-basics-base-and-prime-editing/
Brown GJ, Cañete PF, Wang H, Medhavy A, Bones J, Roco JA, et al. TLR7 gain-of-function genetic variation causes human lupus. Nature 2022;605(7909):349–56.
Hossain MA. CRISPR-Cas9: A fascinating journey from bacterial immune system to human gene editing. Prog Mol Biol Transl Sci 2021;178:63–83.
Anderson MV, Haldrup J, Thomsen EA, Wolff JH, Mikkelsen JG. pegIT - a web-based design tool for prime editing. Nucleic Acids Res 2021;49(W1):W505–9.
Fillatreau S, Manfroi B, Dörner T. Toll-like receptor signalling in B cells during systemic lupus erythematosus. Nat Rev Rheumatol 2021;17(2):98–108.
Frangoul H, Altshuler D, Cappellini MD, Chen YS, Domm J, Eustace BK, et al. CRISPR-Cas9 Gene Editing for Sickle Cell Disease and β-Thalassemia. N Engl J Med 2020;384(3):252–60.
Everette KA, Newby GA, Levine RM, Mayberry K, Jang Y, Mayuranathan T, et al. Ex vivo prime editing of patient haematopoietic stem cells rescues sickle-cell disease phenotypes after engraftment in mice. Nat Biomed Eng 2023;7(5):616–28.
Rezalotfi A, Fritz L, Förster R, Bošnjak B. Challenges of CRISPR-Based Gene Editing in Primary T Cells. Int J Mol Sci 2022;23(3):1689.
Schubert MS, Thommandru B, Woodley J, Turk R, Yan S, Kurgan G, et al. Optimized design parameters for CRISPR Cas9 and Cas12a homology-directed repair. Sci Rep 2021;11(1):19482.
Koeppel J, Weller J, Peets EM, Pallaseni A, Kuzmin I, Raudvere U, et al. Prediction of prime editing insertion efficiencies using sequence features and DNA repair determinants. Nat Biotechnol 2023;41(10):1446–56.
Brown GJ, Cañete PF, Wang H, Medhavy A, Bones J, Roco JA, et al. TLR7 gain-of-function genetic variation causes human lupus. Nature 2022;605(7909):349–56.
Downloads
Posted
Categories
License
Copyright (c) 2025 Jordyn Hansel
This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.
You are free to:
- Share — copy and redistribute the material in any medium or format for any purpose, even commercially.
- Adapt — remix, transform, and build upon the material for any purpose, even commercially.
- The licensor cannot revoke these freedoms as long as you follow the license terms.
Under the following terms:
- Attribution — You must give appropriate credit, provide a link to the license, and indicate if changes were made. You may do so in any reasonable manner, but not in any way that suggests the licensor endorses you or your use.
- No additional restrictions — You may not apply legal terms or technological measures that legally restrict others from doing anything the license
