Lipid nanoparticle-targeted mRNA therapy as a treatment for the inherited metabolic liver disorder arginase deficiency

Abstract

Arginase deficiency is caused by biallelic mutations in arginase 1 (ARG1), the final step of the urea cycle, and results biochemically in hyperargininemia and the presence of guanidino compounds, while it is clinically notable for developmental delays, spastic diplegia, psychomotor function loss, and (uncommonly) death. There is currently no completely effective medical treatment available. While preclinical strategies have been demonstrated, disadvantages with viral-based episomal-expressing gene therapy vectors include the risk of insertional mutagenesis and limited efficacy due to hepatocellular division. Recent advances in messenger RNA (mRNA) codon optimization, synthesis, and encapsulation within biodegradable liver-targeted lipid nanoparticles (LNPs) have potentially enabled a new generation of safer, albeit temporary, treatments to restore liver metabolic function in patients with urea cycle disorders, including ARG1 deficiency. In this study, we applied such technologies to successfully treat an ARG1-deficient murine model. Mice were administered LNPs encapsulating human codon-optimized ARG1 mRNA every 3 d. Mice demonstrated 100% survival with no signs of hyperammonemia or weight loss to beyond 11 wk, compared with controls that perished by day 22. Plasma ammonia, arginine, and glutamine demonstrated good control without elevation of guanidinoacetic acid, a guanidino compound. Evidence of urea cycle activity restoration was demonstrated by the ability to fully metabolize an ammonium challenge and by achieving near-normal ureagenesis; liver arginase activity achieved 54% of wild type. Biochemical and microscopic data showed no evidence of hepatotoxicity. These results suggest that delivery of ARG1 mRNA by liver-targeted nanoparticles may be a viable gene-based therapeutic for the treatment of arginase deficiency.

Ionizable lipid nanoparticles for in utero mRNA delivery

“…Though there are more than 100 postnatal enzyme and protein replacement therapies, these are limited by cost, adverse effects including hypersensitivity and immune response, limitations in reaching the desired organs, and an inability to reverse or rescue already damaged tissue ( 55 , 56 ). Gene therapy, specifically mRNA therapeutics, has recently gained traction as a method of inducing protein or enzyme expression in vivo, with multiple studies demonstrating a longer-term expression of the substrates compared to conventional replacement therapy ( 57 , 58 ). However, research involving prenatal mRNA delivery is in a nascent stage of development.…”

mRNA induced expression of human angiotensin-converting enzyme 2 in mice for the study of the adaptive immune response to severe acute respiratory syndrome coronavirus 2

“…mRNA expression of hACE2 removes these barriers allowing for hACE2 expression in multiple species using a single construct. Additionally, mRNAs can be targeted to specific organs including the liver and lungs [ 49 , 50 ], allowing for localized expression of hACE2 to study the impact of SARS-CoV-2 on specific organs. Finally, as we and others have shown, the mRNA transfection is poorly immunogenic, so repeated administration of the same or different constructs can be administered to the same animal over a prolonged period of time.…”

Genetic Engineering of the Kidney to Permanently Silence MHC Transcripts During ex vivo Organ Perfusion

“…Recently, gene therapeutic approaches have demonstrated to be successful in the treatment of several diseases such as inherited retinal dystrophies, cancer, hemoglobinopathies and neuromuscular diseases using non-viral or viral-based vector technologies (26)(27)(28)(29)(30). Furthermore, several pre-clinical studies show significant progresses in the development of gene therapeutic strategies at organs such as the lung and the liver (31,32). Selection of the method to deliver of the therapeutic vectors remains an essential and crucial hallmark; on the one hand to achieve organ specificity and high transduction efficiencies and on the other hand to ensure maintenance of organ quality during the genetic engineering process.…”