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Open Access | 10.1172/jci.insight.177003
1Department of Pathology, Yale University School of Medicine, New Haven, United States of America
2Division of Rheumatology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, United States of America
3Department of Immunobiology and Yale Stem Cell Center, Yale University School of Medicine, New Haven, United States of America
4Translational Tissue Engineering Center and the Department of Biomedical En, Johns Hopkins University School of Medicine, Baltimore, United States of America
5Department of Rheumatology, Yale University School of Medicine, New Haven, United States of America
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1Department of Pathology, Yale University School of Medicine, New Haven, United States of America
2Division of Rheumatology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, United States of America
3Department of Immunobiology and Yale Stem Cell Center, Yale University School of Medicine, New Haven, United States of America
4Translational Tissue Engineering Center and the Department of Biomedical En, Johns Hopkins University School of Medicine, Baltimore, United States of America
5Department of Rheumatology, Yale University School of Medicine, New Haven, United States of America
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1Department of Pathology, Yale University School of Medicine, New Haven, United States of America
2Division of Rheumatology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, United States of America
3Department of Immunobiology and Yale Stem Cell Center, Yale University School of Medicine, New Haven, United States of America
4Translational Tissue Engineering Center and the Department of Biomedical En, Johns Hopkins University School of Medicine, Baltimore, United States of America
5Department of Rheumatology, Yale University School of Medicine, New Haven, United States of America
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1Department of Pathology, Yale University School of Medicine, New Haven, United States of America
2Division of Rheumatology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, United States of America
3Department of Immunobiology and Yale Stem Cell Center, Yale University School of Medicine, New Haven, United States of America
4Translational Tissue Engineering Center and the Department of Biomedical En, Johns Hopkins University School of Medicine, Baltimore, United States of America
5Department of Rheumatology, Yale University School of Medicine, New Haven, United States of America
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1Department of Pathology, Yale University School of Medicine, New Haven, United States of America
2Division of Rheumatology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, United States of America
3Department of Immunobiology and Yale Stem Cell Center, Yale University School of Medicine, New Haven, United States of America
4Translational Tissue Engineering Center and the Department of Biomedical En, Johns Hopkins University School of Medicine, Baltimore, United States of America
5Department of Rheumatology, Yale University School of Medicine, New Haven, United States of America
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1Department of Pathology, Yale University School of Medicine, New Haven, United States of America
2Division of Rheumatology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, United States of America
3Department of Immunobiology and Yale Stem Cell Center, Yale University School of Medicine, New Haven, United States of America
4Translational Tissue Engineering Center and the Department of Biomedical En, Johns Hopkins University School of Medicine, Baltimore, United States of America
5Department of Rheumatology, Yale University School of Medicine, New Haven, United States of America
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1Department of Pathology, Yale University School of Medicine, New Haven, United States of America
2Division of Rheumatology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, United States of America
3Department of Immunobiology and Yale Stem Cell Center, Yale University School of Medicine, New Haven, United States of America
4Translational Tissue Engineering Center and the Department of Biomedical En, Johns Hopkins University School of Medicine, Baltimore, United States of America
5Department of Rheumatology, Yale University School of Medicine, New Haven, United States of America
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1Department of Pathology, Yale University School of Medicine, New Haven, United States of America
2Division of Rheumatology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, United States of America
3Department of Immunobiology and Yale Stem Cell Center, Yale University School of Medicine, New Haven, United States of America
4Translational Tissue Engineering Center and the Department of Biomedical En, Johns Hopkins University School of Medicine, Baltimore, United States of America
5Department of Rheumatology, Yale University School of Medicine, New Haven, United States of America
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1Department of Pathology, Yale University School of Medicine, New Haven, United States of America
2Division of Rheumatology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, United States of America
3Department of Immunobiology and Yale Stem Cell Center, Yale University School of Medicine, New Haven, United States of America
4Translational Tissue Engineering Center and the Department of Biomedical En, Johns Hopkins University School of Medicine, Baltimore, United States of America
5Department of Rheumatology, Yale University School of Medicine, New Haven, United States of America
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1Department of Pathology, Yale University School of Medicine, New Haven, United States of America
2Division of Rheumatology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, United States of America
3Department of Immunobiology and Yale Stem Cell Center, Yale University School of Medicine, New Haven, United States of America
4Translational Tissue Engineering Center and the Department of Biomedical En, Johns Hopkins University School of Medicine, Baltimore, United States of America
5Department of Rheumatology, Yale University School of Medicine, New Haven, United States of America
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1Department of Pathology, Yale University School of Medicine, New Haven, United States of America
2Division of Rheumatology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, United States of America
3Department of Immunobiology and Yale Stem Cell Center, Yale University School of Medicine, New Haven, United States of America
4Translational Tissue Engineering Center and the Department of Biomedical En, Johns Hopkins University School of Medicine, Baltimore, United States of America
5Department of Rheumatology, Yale University School of Medicine, New Haven, United States of America
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1Department of Pathology, Yale University School of Medicine, New Haven, United States of America
2Division of Rheumatology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, United States of America
3Department of Immunobiology and Yale Stem Cell Center, Yale University School of Medicine, New Haven, United States of America
4Translational Tissue Engineering Center and the Department of Biomedical En, Johns Hopkins University School of Medicine, Baltimore, United States of America
5Department of Rheumatology, Yale University School of Medicine, New Haven, United States of America
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1Department of Pathology, Yale University School of Medicine, New Haven, United States of America
2Division of Rheumatology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, United States of America
3Department of Immunobiology and Yale Stem Cell Center, Yale University School of Medicine, New Haven, United States of America
4Translational Tissue Engineering Center and the Department of Biomedical En, Johns Hopkins University School of Medicine, Baltimore, United States of America
5Department of Rheumatology, Yale University School of Medicine, New Haven, United States of America
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1Department of Pathology, Yale University School of Medicine, New Haven, United States of America
2Division of Rheumatology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, United States of America
3Department of Immunobiology and Yale Stem Cell Center, Yale University School of Medicine, New Haven, United States of America
4Translational Tissue Engineering Center and the Department of Biomedical En, Johns Hopkins University School of Medicine, Baltimore, United States of America
5Department of Rheumatology, Yale University School of Medicine, New Haven, United States of America
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1Department of Pathology, Yale University School of Medicine, New Haven, United States of America
2Division of Rheumatology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, United States of America
3Department of Immunobiology and Yale Stem Cell Center, Yale University School of Medicine, New Haven, United States of America
4Translational Tissue Engineering Center and the Department of Biomedical En, Johns Hopkins University School of Medicine, Baltimore, United States of America
5Department of Rheumatology, Yale University School of Medicine, New Haven, United States of America
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1Department of Pathology, Yale University School of Medicine, New Haven, United States of America
2Division of Rheumatology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, United States of America
3Department of Immunobiology and Yale Stem Cell Center, Yale University School of Medicine, New Haven, United States of America
4Translational Tissue Engineering Center and the Department of Biomedical En, Johns Hopkins University School of Medicine, Baltimore, United States of America
5Department of Rheumatology, Yale University School of Medicine, New Haven, United States of America
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1Department of Pathology, Yale University School of Medicine, New Haven, United States of America
2Division of Rheumatology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, United States of America
3Department of Immunobiology and Yale Stem Cell Center, Yale University School of Medicine, New Haven, United States of America
4Translational Tissue Engineering Center and the Department of Biomedical En, Johns Hopkins University School of Medicine, Baltimore, United States of America
5Department of Rheumatology, Yale University School of Medicine, New Haven, United States of America
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1Department of Pathology, Yale University School of Medicine, New Haven, United States of America
2Division of Rheumatology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, United States of America
3Department of Immunobiology and Yale Stem Cell Center, Yale University School of Medicine, New Haven, United States of America
4Translational Tissue Engineering Center and the Department of Biomedical En, Johns Hopkins University School of Medicine, Baltimore, United States of America
5Department of Rheumatology, Yale University School of Medicine, New Haven, United States of America
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1Department of Pathology, Yale University School of Medicine, New Haven, United States of America
2Division of Rheumatology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, United States of America
3Department of Immunobiology and Yale Stem Cell Center, Yale University School of Medicine, New Haven, United States of America
4Translational Tissue Engineering Center and the Department of Biomedical En, Johns Hopkins University School of Medicine, Baltimore, United States of America
5Department of Rheumatology, Yale University School of Medicine, New Haven, United States of America
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1Department of Pathology, Yale University School of Medicine, New Haven, United States of America
2Division of Rheumatology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, United States of America
3Department of Immunobiology and Yale Stem Cell Center, Yale University School of Medicine, New Haven, United States of America
4Translational Tissue Engineering Center and the Department of Biomedical En, Johns Hopkins University School of Medicine, Baltimore, United States of America
5Department of Rheumatology, Yale University School of Medicine, New Haven, United States of America
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Andrade, F.
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1Department of Pathology, Yale University School of Medicine, New Haven, United States of America
2Division of Rheumatology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, United States of America
3Department of Immunobiology and Yale Stem Cell Center, Yale University School of Medicine, New Haven, United States of America
4Translational Tissue Engineering Center and the Department of Biomedical En, Johns Hopkins University School of Medicine, Baltimore, United States of America
5Department of Rheumatology, Yale University School of Medicine, New Haven, United States of America
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Published June 18, 2024 - More info
A defining feature of systemic lupus erythematosus (SLE) is loss of tolerance to self-DNA, and DNASE1L3 deficiency, the main enzyme responsible for chromatin degradation in blood, is also associated with SLE. This association includes an ultra-rare pediatric population with DNASE1L3 deficiency who develop SLE, adult patients with loss of function variants of DNASE1L3 who are at a higher risk for SLE, and patients with sporadic SLE who have neutralizing autoantibodies to DNASE1L3. To mitigate the pathogenic effects of inherited and acquired DNASE1L3 deficiencies, we engineered a long-acting enzyme biologic with dual DNASE1/DNASE1L3 activity that is resistant to DNASE1 and DNASE1L3 inhibitors. Notably, we found that the biologic prevented the development of lupus in Dnase1–/–/Dnase1L3–/– double knockout mice and rescued animals from death in pristane-induced lupus. Finally, we confirmed that the human isoform of the enzyme biologic was not recognized by autoantibodies in SLE and efficiently degrades genomic and mitochondrial cell free DNA, as well as microparticle DNA, in SLE plasma. Our findings suggest that autoimmune diseases characterized by aberrant DNA accumulation, such as SLE, can be effectively treated with a replacement DNASE tailored to bypass pathogenic mechanisms, both genetic and acquired, that restrict DNASE1L3 activity.