Exploring RNA therapeutics for urea cycle disorders

Abstract

RNA has triggered a significant shift in modern medicine, providing a promising way to revolutionize disease treatment methods. Different therapeutic RNA modalities have shown promise to replace, supplement, correct, suppress, or eliminate the expression of a targeted gene. Currently, there are 22 RNA-based drugs approved for clinical use, including the COVID-19 mRNA vaccines, whose unprecedented worldwide success has meant a definitive boost in the RNA research field. Urea cycle disorders (UCD), liver diseases with high mortality and morbidity, may benefit from the progress achieved, as different genetic payloads have been successfully targeted to liver using viral vectors, N-acetylgalactosamine (GalNAc) conjugations or lipid nanoparticles (LNP). This review explores the potential of RNA-based medicines for UCD and the ongoing development of applications targeting specific gene defects, enzymes, or transporters taking part in the urea cycle. Notably, LNP-formulated mRNA therapy has been assayed preclinically for citrullinemia type I (CTLN1), adolescent and adult citrin deficiency, argininosuccinic aciduria, arginase deficiency and ornithine transcarbamylase deficiency, in the latter case has progressed to the clinical trials phase.

Keywords: antisense oligonucleotides; mRNA therapy; ornithine transcarbamylase deficiency; pseudoexon; splicing; urea cycle.

FIGURE 1

RNA therapies in development for urea cycle defects. AACD, adolescent and adult citrin deficiency; ARG1, arginase; ASA, argininosuccinic aciduria; ASL, argininosuccinate lyase; ASS1, argininosuccinate synthetase; CPS1, carbamoylphosphate synthetase I; CTLN1, citrullinemia type 1; HMT, hybrid mRNA Technology; LNP, lipid nanoparticles; NAGS, N‐acetyl glutamate synthase; ORNT1, ornithine translocase; OTC, ornithine transcarbamylase; OTCD, ornithine transcarbamylase deficiency; SSO, splice switching antisense oligonucleotides. All therapies are in preclinical or clinical stage for UCD and/or other disorders, as specified in Table 1.