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.
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