Delivering the message: mRNA replacement reaches the liver in Niemann-Pick type C1 disease

Niemann-Pick type C1 (NPC1) disease is an autosomal recessive lysosomal storage dis order affecting both neuronal and periph eral tissues. Several NPC1 mutations impair cholesterol export from late endosomes and lysosomes, leading to lipid accumulation, impaired autophagy, mitochondrial stress, inflammation, and progressive injury in the liver and central nervous system. Although the conditions can be severe, available therapeutic options remain limited. In this issue of Molecular Therapy Nucleic Acids, Koufer and colleagues re ported results from an in vivo evaluation of an mRNA-based NPC1 replacement ther apy. In detail, using lipid nanoparticles (LNPs) carrying a codon-optimized murine Npc1 mRNA (Co-Npc1:LNP), they restored a correctly folded and lysosome-targeted NPC1 1 (Figure 1). This study shows that temporary expression of a large lysosomal membrane protein can rapidly improve sys temic defects. However, the durability of the effects, repeat dosing, and delivery to the nervous system must be evaluated.