Custom-designed lipid-based nanoparticles efficiently deliver mRNA to reverse the pathogenesis of LAL deficiency in a preclinical model

Lysosomal acid lipase (LAL) is a crucial enzyme responsible for the hydrolysis of triglycerides (TGs) and cholesteryl esters (CEs) in the lysosomes. LAL deficiency results in the extensive storage of CEs and TGs in the liver and the spleen, inducing hepatosplenomegaly, and can be a life-threatening condition with patients rarely surviving beyond 6 months of age in the most aggressive form. Using messenger ribonucleic acid (mRNA) for protein replacement is an innovative approach to treating LAL deficiency. Here, we describe the development of a new lipid-based nanoparticle (LNP) formulation capable of efficiently delivering LAL mRNA and restoring LAL activity in affected organs mediating significant reversal of the pathological progression in a highly predictive preclinical model. A combinatorial library of mRNA-LNPs was generated and screened both in vitro and in vivo to yield a new formulation with a higher potency than an FDA-approved MC3-based nano-formulation. In vivo evaluation revealed that the new formulation could promote a more sustained and superior LAL expression. Multiple injection regimen was able to mitigate hepatosplenomegaly and reduce the lipid accumulation of CEs and TGs by 20-30% in the liver and 50% in the spleen. Furthermore, liver inflammation processes and development of fibrosis were significantly diminished. These findings provide strong evidence that mRNA-LNP is a very promising approach for the chronic treatment of LAL deficiency and support the clinical translation of mRNA therapy to overcome side effects and challenges encountered with traditional enzyme replacement therapies.