Mucopolysaccharidosis type I-Hurler (MPS I-H) is a severe lysosomal storage disorder caused by α-L-iduronidase (IDUA) deficiency, leading to glycosaminoglycan (GAG) accumulation and progressive multisystem dysfunction, including the central nervous system (CNS). Early hematopoietic stem cell transplantation remains the primary disease-modifying intervention for MPS I-H despite its clinical challenges. Conventional enzyme replacement therapy (ERT), which has limited CNS efficacy due to blood-brain barrier (BBB) restrictions, is being addressed by the development of novel BBB-penetrating ERT platforms. Recently, mRNA therapy has become a promising treatment option for rare genetic diseases by enabling the in vivo supplementation of defective or deficient proteins to ameliorate the disease phenotype. To evaluate mRNA therapy for MPS I-H, we screened ionizable lipids to develop lipid nanoparticle systems optimized for hepatic delivery, which were subsequently used to encapsulate mRNA encoding human IDUA (hIDUA) fused to a validated BBB-penetrating melanotransferrin peptide (MTfp). This formulation was intravenously administered to neonatal MPS I-H mice at a dose of 1.0 mg/kg every 2 weeks for 4 months. The treatment significantly increased IDUA enzyme activity in both the serum and liver. Concurrently, it reduced GAG accumulation in the urine, peripheral tissues, and partial CNS regions (olfactory bulbs, hippocampus, and cerebellum). Furthermore, the treatment significantly improved cardiac and skeletal development, as assessed by echocardiography and micro-computed tomography, respectively. Notably, it also enhanced cognitive function, as evidenced by the improved performance in the Delayed-Matching-to-Place dry maze test. Our findings demonstrate that LNP-MTfp-hIDUA treatment effectively ameliorates key pathological features and promotes neurodevelopment in MPS I-H, establishing a promising and safe therapeutic strategy for this disorder.
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