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Lipid nanoparticle-mediated base-editing of the Hao1 gene achieves sustainable primary hyperoxaluria type 1 therapy in rats

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Science China Life Sciences 2024年第12期67卷 2575-2586页

作者： Dexin Zhang Rui Zheng Zhoutong Chen Liren Wang Xi Chen Lei Yang Yanan Huo Shuming Yin Dan Zhang Jiaxin Huang Xingang Cui Dali Li Hongquan Geng Department of Urology Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine Department of Urology Children's Hospital of Fudan University Shanghai Frontiers Science Center of Genome Editing and Cell Therapy Shanghai Key Laboratory of Regulatory Biology Institute of Biomedical Sciences and School of Life Sciences East China Normal University

Primary hyperoxaluria type 1(PH1) is a severe hereditary disease, leading to the accumulation of oxalate in multiple organs, particularly the kidney. hydroxyacid oxidase 1(HAO1), a pivotal gene involved in oxalate production, is an approved target for the treatment of PH1. In this study, we demonstrated the discovery of several novel therapeutic sites of the Hao1 gene and the efficient editing of Hao1c.290-2 A in vivo with lipid nanoparticles(LNP) delivered adenine base editing(ABE) mRNA. A single infusion of LNP-ABE resulted in a near-complete knockout of Hao1 in the liver, leading to the sustainable normalization of urinary oxalate(for at least 6 months) and complete rescue of the pathophysiology in PH1 rats. Additionally, a significant correlation between Hao1 editing efficiency and urinary oxalate levels was observed and over 60% Hao1 editing efficiency was required to achieve the normalization of urinary oxalate in PH1 rats. These findings suggest that the LNP-mediated base-editing of Hao1c.290-2 A is an efficient and safe approach to PH1 therapy, highlighting its potential utility in clinical settings.

关键词： primary hyperoxaluria type 1 lipid nanoparticles hydroxyacid oxidase 1 base editing

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Multiplex gene editing reduces oxalate production in primary hyperoxaluria type 1

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Zoological Research 2023年第6期44卷 993-1002页

作者： Rui Zheng De-Xin Zhang Yan-Jiao Shao Xiao-Liang Fang Lei Yang Ya-Nan Huo Da-Li Li Hong-Quan Geng Department of Pediatric Urology Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of MedicineShanghai 200092China Shanghai Key Laboratory of Regulatory Biology Institute of Biomedical Sciences and School of Life SciencesEast China Normal UniversityShanghai 200241China Division of Pediatric Urology Children’s Hospital of Fudan UniversityShanghai 201102China

Targeting key enzymes that generate oxalate precursors or substrates is an alternative strategy to eliminate primary hyperoxaluria type I(PH1),the most common and lifethreatening type of primary *** compact Clustered Regularly Interspaced Short Palindromic Repeats(CRISPR)from the Prevotella and Francisella 1(Cpf1)protein simplifies multiplex gene editing and allows for all-in-one adeno-associated virus(AAV)*** hypothesized that the multiplex capabilities of the Cpf1system could help minimize oxalate formation in PH1 by simultaneously targeting the hepatic hydroxyacid oxidase 1(Hao1)and lactate dehydrogenase A(Ldha)*** cohorts included treated PH1 rats(Agxt Q84X rats injected with AAV-AsCpf1 at 7 days of age),phosphate-buffered saline(PBS)-injected PH1 rats,untreated PH1 rats,and age-matched wild-type(WT)*** most efficient and specific CRISPR RNA(crRNA)pairs targeting the rat Hao1and Ldha genes were initially screened ex *** vivo experiments demonstrated efficient genome editing of the Hao1 and Ldha genes,primarily resulting in small *** resulted in decreased transcription and translational expression of Hao1 and *** significantly reduced urine oxalate levels,reduced kidney damage,and alleviated nephrocalcinosis in rats with *** liver toxicity,ex-liver genome editing,or obvious offtarget effects were *** demonstrated the AAVAsCpf1 system can target multiple genes and rescue the pathogenic phenotype in PH1,serving as a proof-ofconcept for the development of multiplex genome editingbased gene therapy.

关键词： Hyperoxaluria Genome editing Lactate dehydrogenase hydroxyacid oxidase 1

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