DataSheet1_Phenylalanine hydroxylase mRNA rescues the phenylketonuria phenotype in mice.docx

Phenylketonuria (PKU) is an inborn error of metabolism caused by a deficiency in functional phenylalanine hydroxylase (PAH), resulting in accumulation of phenylalanine (Phe) in patients’ blood and organs. Affected patients encounter severe developmental delay, neurological deficits, and behavioral abnormalities when not treated. Early diagnosis and treatment are extremely important; newborn screening programs have been implemented in most countries to ensure early identification of patients with PKU. Despite available treatment options, several challenges remain: life-long adherence to a strict diet, approval of some medications for adults only, and lack of response to these therapies in a subpopulation of patients. Therefore, there is an urgent need for treatment alternatives. An mRNA-based approach tested in PKU mice showed a fast reduction in the accumulation of Phe in serum, liver and brain, the most significant organ affected. Repeated injections of LNP-formulated mouse PAH mRNA rescued PKU mice from the disease phenotype for a prolonged period of time. An mRNA-based approach could improve the quality of life tremendously in PKU patients of all ages by replacing standard-of-care treatments.

苯丙酮尿症（Phenylketonuria, PKU）是一种因功能性苯丙氨酸羟化酶（phenylalanine hydroxylase, PAH）缺乏引发的先天性代谢紊乱，可导致患者血液与器官内苯丙氨酸（phenylalanine, Phe）蓄积。未接受治疗的患者会出现严重发育迟缓、神经功能缺损及行为异常。早期诊断与治疗极为关键；目前多数国家已推行新生儿筛查项目，以确保及早确诊PKU患者。尽管已有可供选择的治疗方案，但仍存在多项挑战：需终身严格遵循特殊饮食、部分药物仅获批用于成人人群，且部分患者对现有治疗无响应。因此，亟需开发新型替代治疗手段。在PKU小鼠模型中测试的基于信使核糖核酸（messenger RNA, mRNA）的疗法，可快速降低血清、肝脏与大脑（其中大脑为受影响最显著的器官）内的苯丙氨酸蓄积水平。重复注射脂质纳米颗粒（lipid nanoparticle, LNP）包裹的小鼠PAH mRNA，可长期缓解PKU小鼠的疾病表型。基于mRNA的疗法可通过替代标准治疗方案，极大改善各年龄段PKU患者的生活质量。