Lipid Nanoparticle-Delivered mRNA Therapy Corrects Neonatal Murine MPS I-H

Area of Science:

• Biochemistry
• Genetics
• Pharmacology

Background:

• Mucopolysaccharidosis type I-Hurler (MPS I-H) is a severe genetic disorder caused by alpha-L-iduronidase (IDUA) deficiency, leading to toxic glycosaminoglycan (GAG) buildup.
• Current treatments like enzyme replacement therapy (ERT) struggle with blood-brain barrier (BBB) penetration, limiting central nervous system (CNS) efficacy.
• mRNA therapy offers a novel approach for in vivo protein supplementation to address genetic deficiencies.

Purpose of the Study:

• To develop and evaluate an mRNA-based therapy for MPS I-H, focusing on BBB penetration and therapeutic efficacy.
• To optimize lipid nanoparticle (LNP) systems for hepatic delivery of mRNA encoding a BBB-penetrating fusion protein.
• To assess the impact of the novel therapy on GAG accumulation, organ development, and cognitive function in MPS I-H mouse models.

Main Methods:

• Screening of ionizable lipids to create LNP systems for efficient hepatic delivery.
• Encapsulation of mRNA encoding human IDUA fused to a melanotransferrin peptide (MTfp) into optimized LNPs (LNP-MTfp-hIDUA).
• Intravenous administration of LNP-MTfp-hIDUA to neonatal MPS I-H mice, followed by comprehensive biochemical, imaging, and behavioral assessments.

Main Results:

• Significant increase in IDUA enzyme activity in serum and liver following LNP-MTfp-hIDUA treatment.
• Substantial reduction in GAG accumulation in urine, peripheral tissues, and key CNS regions (olfactory bulbs, hippocampus, cerebellum).
• Marked improvements in cardiac and skeletal development, alongside enhanced cognitive function in treated MPS I-H mice.

Conclusions:

• LNP-MTfp-hIDUA therapy demonstrates significant potential for treating MPS I-H by effectively delivering therapeutic mRNA across the BBB.
• The treatment ameliorates major pathological features, including GAG storage and organ dysfunction, and promotes neurodevelopment.
• This mRNA-based strategy represents a promising and safe therapeutic avenue for MPS I-H and potentially other lysosomal storage disorders affecting the CNS.