Perez-Garcia Carlos G, Diaz-Trelles Ramon, Vega Jerel Boyd, Bao Yanjie, Sablad Marciano, Limphong Patty, Chikamatsu Simon, Yu Hailong, Taylor Wendy, Karmali Priya P, Tachikawa Kiyoshi, Chivukula Padmanabh
Arcturus Therapeutics, Inc., 10628 Science Center Drive, Suite 250, San Diego, CA 92121, USA.
Mol Ther Nucleic Acids. 2022 Feb 28;28:87-98. doi: 10.1016/j.omtn.2022.02.020. eCollection 2022 Jun 14.
Phenylketonuria (PKU) is an inborn error caused by deficiencies in phenylalanine (Phe) metabolism. Mutations in the phenylalanine hydroxylase (PAH) gene are the main cause of the disease whose signature hallmarks of toxically elevated levels of Phe accumulation in plasma and organs such as the brain, result in irreversible intellectual disability. Here, we present a unique approach to treating PKU deficiency by using an mRNA replacement therapy. A full-length mRNA encoding human PAH (hPAH) is encapsulated in our proprietary lipid nanoparticle LUNAR and delivered to a mouse model that carries a missense mutation in the mouse PAH gene. Animals carrying this missense mutation develop hyperphenylalanemia and hypotyrosinemia in plasma, two clinical features commonly observed in the clinical presentation of PKU. We show that intravenous infusion of LUNAR-hPAH mRNA can generate high levels of hPAH protein in hepatocytes and restore the Phe metabolism in the mouse model. Together, these data establish a proof of principle of a novel mRNA replacement therapy to treat PKU.
苯丙酮尿症（PKU）是一种由苯丙氨酸（Phe）代谢缺陷引起的先天性疾病。苯丙氨酸羟化酶（PAH）基因突变是该疾病的主要病因，其标志性特征是血浆和大脑等器官中Phe积累水平毒性升高，导致不可逆转的智力残疾。在此，我们展示了一种通过使用mRNA替代疗法治疗PKU缺陷的独特方法。编码人PAH（hPAH）的全长mRNA被封装在我们专有的脂质纳米颗粒LUNAR中，并递送至携带小鼠PAH基因错义突变的小鼠模型。携带这种错义突变的动物血浆中会出现高苯丙氨酸血症和低酪氨酸血症，这是PKU临床表现中常见的两个临床特征。我们表明，静脉注射LUNAR-hPAH mRNA可在肝细胞中产生高水平的hPAH蛋白，并恢复小鼠模型中的Phe代谢。总之，这些数据确立了一种治疗PKU的新型mRNA替代疗法的原理证明。
