Gene therapy enhances deoxyribonuclease I treatment in antimyeloperoxidase glomerulonephritis.

Cao Le, A; Oudin, V; Dick, J; Alikhan, MA; Gottschalk, TA; Lu, L; Lawlor, KE; Koo Yuk Cheong, D; Mandwie, M; Alexander, IE; Kitching, AR; Gan, P-Y; Logan, GJ; O'Sullivan, KM

Gene therapy enhances deoxyribonuclease I treatment in antimyeloperoxidase glomerulonephritis.

Cao Le, A Oudin, V Dick, J Alikhan, MA Gottschalk, TA Lu, L Lawlor, KE Koo Yuk Cheong, D Mandwie, M

Alexander, IE Kitching, AR Gan, P-Y Logan, GJ O'Sullivan, KM

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Publisher:: AMER SOC CLINICAL INVESTIGATION INC
Publication Type:: Journal Article
Citation:: JCI Insight, 2025, 10, (15), pp. e188951
Issue Date:: 2025-08-08

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Field	Value	Language
dc.contributor.author	Cao Le, A
dc.contributor.author	Oudin, V
dc.contributor.author	Dick, J
dc.contributor.author	Alikhan, MA
dc.contributor.author	Gottschalk, TA
dc.contributor.author	Lu, L
dc.contributor.author	Lawlor, KE
dc.contributor.author	Koo Yuk Cheong, D
dc.contributor.author	Mandwie, M https://orcid.org/0000-0002-4165-4276
dc.contributor.author	Alexander, IE
dc.contributor.author	Kitching, AR
dc.contributor.author	Gan, P-Y
dc.contributor.author	Logan, GJ
dc.contributor.author	O'Sullivan, KM
dc.date.accessioned	2026-02-03T08:46:28Z
dc.date.available	2025-06-26
dc.date.available	2026-02-03T08:46:28Z
dc.date.issued	2025-08-08
dc.identifier.citation	JCI Insight, 2025, 10, (15), pp. e188951
dc.identifier.issn	2379-3708
dc.identifier.issn	2379-3708
dc.identifier.uri	http://hdl.handle.net/10453/192825
dc.description.abstract	Extracellular DNA (ecDNA) released from injured and dying cells powerfully induces injurious inflammation. In this study we define the role of ecDNA in systemic vasculitis affecting the kidney, using human kidney biopsies and murine models of myeloperoxidase anti-neutrophil cytoplasmic antibody-associated glomerulonephritis (MPO-ANCA GN). Twice daily administration of intravenous deoxyribonuclease I (ivDNase I) in 2 models of anti-MPO GN reduced glomerular deposition of ecDNA, histological injury, leukocyte infiltration, and NETosis. Comprehensive investigation into DNase I modes of action revealed that after exposure to MPO, DNase I reduced lymph node DC numbers and their activation status, resulting in decreased frequency of MPO-specific CD4+ effector T cells (IFN-γ and IL-17A producing) and reductions in dermal anti-MPO delayed type hypersensitivity responses. To overcome the translational obstacle of the short half-life of DNase I (<5 hours), we tested an adeno-associated viral vector encoding DNase I. This method of DNase I delivery was more effective, as in addition to the histological and antiinflammatory changes described above, a single vector treatment also reduced circulating MPO-ANCA titers and albuminuria. These results indicate ecDNA is a potent driver of anti-MPO GN and DNase I is a potential therapeutic that can be delivered using gene technology.
dc.format	Electronic-eCollection
dc.language	eng
dc.publisher	AMER SOC CLINICAL INVESTIGATION INC
dc.relation.ispartof	JCI Insight
dc.relation.isbasedon	10.1172/jci.insight.188951
dc.rights	info:eu-repo/semantics/openAccess
dc.subject.classification	32 Biomedical and clinical sciences
dc.subject.classification	42 Health sciences
dc.subject.mesh	Deoxyribonuclease I
dc.subject.mesh	Animals
dc.subject.mesh	Glomerulonephritis
dc.subject.mesh	Mice
dc.subject.mesh	Peroxidase
dc.subject.mesh	Humans
dc.subject.mesh	Genetic Therapy
dc.subject.mesh	Disease Models, Animal
dc.subject.mesh	Antibodies, Antineutrophil Cytoplasmic
dc.subject.mesh	Male
dc.subject.mesh	Female
dc.subject.mesh	Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis
dc.subject.mesh	Kidney
dc.subject.mesh	Mice, Inbred C57BL
dc.subject.mesh	Kidney
dc.subject.mesh	Animals
dc.subject.mesh	Mice, Inbred C57BL
dc.subject.mesh	Humans
dc.subject.mesh	Mice
dc.subject.mesh	Glomerulonephritis
dc.subject.mesh	Disease Models, Animal
dc.subject.mesh	Deoxyribonuclease I
dc.subject.mesh	Peroxidase
dc.subject.mesh	Antibodies, Antineutrophil Cytoplasmic
dc.subject.mesh	Female
dc.subject.mesh	Male
dc.subject.mesh	Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis
dc.subject.mesh	Genetic Therapy
dc.subject.mesh	Deoxyribonuclease I
dc.subject.mesh	Animals
dc.subject.mesh	Glomerulonephritis
dc.subject.mesh	Mice
dc.subject.mesh	Peroxidase
dc.subject.mesh	Humans
dc.subject.mesh	Genetic Therapy
dc.subject.mesh	Disease Models, Animal
dc.subject.mesh	Antibodies, Antineutrophil Cytoplasmic
dc.subject.mesh	Male
dc.subject.mesh	Female
dc.subject.mesh	Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis
dc.subject.mesh	Kidney
dc.subject.mesh	Mice, Inbred C57BL
dc.title	Gene therapy enhances deoxyribonuclease I treatment in antimyeloperoxidase glomerulonephritis.
dc.type	Journal Article
utslib.citation.volume	10
utslib.location.activity	United States
pubs.organisational-group	University of Technology Sydney
pubs.organisational-group	University of Technology Sydney/Faculty of Science
utslib.copyright.status	open_access	*
dc.rights.license	This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0). To view a copy of this license, visit https://creativecommons.org/licenses/by/4.0/
dc.date.updated	2026-02-03T08:46:22Z
pubs.issue	15
pubs.publication-status	Published online
pubs.volume	10
utslib.citation.issue	15

Abstract:

Extracellular DNA (ecDNA) released from injured and dying cells powerfully induces injurious inflammation. In this study we define the role of ecDNA in systemic vasculitis affecting the kidney, using human kidney biopsies and murine models of myeloperoxidase anti-neutrophil cytoplasmic antibody-associated glomerulonephritis (MPO-ANCA GN). Twice daily administration of intravenous deoxyribonuclease I (ivDNase I) in 2 models of anti-MPO GN reduced glomerular deposition of ecDNA, histological injury, leukocyte infiltration, and NETosis. Comprehensive investigation into DNase I modes of action revealed that after exposure to MPO, DNase I reduced lymph node DC numbers and their activation status, resulting in decreased frequency of MPO-specific CD4+ effector T cells (IFN-γ and IL-17A producing) and reductions in dermal anti-MPO delayed type hypersensitivity responses. To overcome the translational obstacle of the short half-life of DNase I (<5 hours), we tested an adeno-associated viral vector encoding DNase I. This method of DNase I delivery was more effective, as in addition to the histological and antiinflammatory changes described above, a single vector treatment also reduced circulating MPO-ANCA titers and albuminuria. These results indicate ecDNA is a potent driver of anti-MPO GN and DNase I is a potential therapeutic that can be delivered using gene technology.

Please use this identifier to cite or link to this item:

http://hdl.handle.net/10453/192825