Zhang Dexin, Zheng Rui, Chen Zhoutong, Wang Liren, Chen Xi, Yang Lei, Huo Yanan, Yin Shuming, Zhang Dan, Huang Jiaxin, Cui Xingang, Li Dali, Geng Hongquan
Department of Urology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, China.
Department of Urology, Children's Hospital of Fudan University, Shanghai, 201100, China.
Sci China Life Sci. 2024 Dec;67(12):2575-2586. doi: 10.1007/s11427-024-2697-3. Epub 2024 Oct 16.
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 Hao1 c.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 patho-physiology 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 Hao1 c.290-2 A is an efficient and safe approach to PH1 therapy, highlighting its potential utility in clinical settings.
1型原发性高草酸尿症（PH1）是一种严重的遗传性疾病，会导致草酸盐在多个器官尤其是肾脏中蓄积。羟基酸氧化酶1（HAO1）是参与草酸盐生成的关键基因，是治疗PH1的一个已获批准的靶点。在本研究中，我们展示了Hao1基因几个新治疗位点的发现，以及利用脂质纳米颗粒（LNP）递送腺嘌呤碱基编辑（ABE）mRNA在体内对Hao1 c.290-2A进行有效编辑。单次注射LNP-ABE导致肝脏中Hao1几乎完全敲除，使尿草酸盐持续正常化（至少6个月），并完全挽救了PH1大鼠的病理生理学状态。此外，观察到Hao1编辑效率与尿草酸盐水平之间存在显著相关性，并且需要超过60%的Hao1编辑效率才能使PH1大鼠的尿草酸盐正常化。这些发现表明，LNP介导的Hao1 c.290-2A碱基编辑是一种治疗PH1的有效且安全的方法，突出了其在临床环境中的潜在应用价值。
