Department of Pediatrics, Maastricht University Medical Center+, Maastricht, the Netherlands.
GROW, Maastricht University, Maastricht, the Netherlands.
J Inherit Metab Dis. 2022 Jul;45(4):748-758. doi: 10.1002/jimd.12512. Epub 2022 May 27.
Messenger RNA (mRNA) has emerged as a novel therapeutic approach for inborn errors of metabolism. Classic galactosemia (CG) is an inborn error of galactose metabolism caused by a severe deficiency of galactose-1-phosphate:uridylyltransferase (GALT) activity leading to neonatal illness and chronic impairments affecting the brain and female gonads. In this proof of concept study, we used our zebrafish model for CG to evaluate the potential of human GALT mRNA (hGALT mRNA) packaged in two different lipid nanoparticles to restore GALT expression and activity at early stages of development. Both one cell-stage and intravenous single-dose injections resulted in hGALT protein expression and enzyme activity in the CG zebrafish (galt knockout) at 5 days post fertilization (dpf). Moreover, the levels of galactose-1-phosphate (Gal-1-P) and galactonate, metabolites that accumulate because of the deficiency, showed a decreasing trend. LNP-packaged mRNA was effectively translated and processed in the CG zebrafish without signs of toxicity. This study shows that mRNA therapy restores GALT protein and enzyme activity in the CG zebrafish model, and that the zebrafish is a suitable system to test this approach. Further studies are warranted to assess whether repeated injections safely mitigate the chronic impairments of this disease.
信使 RNA（mRNA）已成为治疗先天性代谢错误的一种新方法。经典半乳糖血症（CG）是一种由半乳糖-1-磷酸：尿苷二磷酸转移酶（GALT）活性严重缺乏引起的先天性代谢错误，导致新生儿疾病和影响大脑和女性性腺的慢性损伤。在这项概念验证研究中，我们使用 CG 的斑马鱼模型来评估两种不同脂质纳米颗粒包装的人 GALT mRNA（hGALT mRNA）在早期发育阶段恢复 GALT 表达和活性的潜力。在受精后 5 天（5 dpf），单细胞期和静脉单次剂量注射均可在 CG 斑马鱼（galt 敲除）中表达 hGALT 蛋白和酶活性。此外，由于缺乏而积累的代谢物半乳糖-1-磷酸（Gal-1-P）和半乳糖酸盐的水平呈下降趋势。包装在 LNP 中的 mRNA 有效地在 CG 斑马鱼中翻译和加工，没有毒性迹象。这项研究表明，mRNA 疗法可恢复 CG 斑马鱼模型中的 GALT 蛋白和酶活性，并且斑马鱼是测试这种方法的合适系统。需要进一步的研究来评估重复注射是否能安全减轻这种疾病的慢性损伤。
