mRNA-based enzyme replacement for propionic acidaemia

Abstract

Propionic acidaemia is an autosomal recessive metabolic disorder, typically presenting in neonates with vomiting, dehydration, feeding issues and rapid physical decline. Without prompt early intervention, symptoms can progress to seizures, coma and even death. Long-term complications include growth failure, neurological damage, heart and immune dysfunction, and pancreatitis. Propionic acidaemia is caused by pathogenic variants in two genes, PCCA or PCCB, which encode the α and β subunits of propionyl-coenzyme A (CoA) carboxylase (PCC), respectively. PCC, a mitochondrial enzyme consisting of six subunits each of PCCA and PCCB, converts propionyl-CoA to methylmalonyl-CoA. PCC deficiency leads to the toxic accumulation of propionyl-CoA and organic acids, resulting in an intoxication-type metabolic crisis. Aside from liver transplantation, management of propionic acidaemia focuses on survival and then quality of life; no therapies specifically target the underlying enzymatic defect through metabolic correction. A paper published in Nature Communications in 2020 reported the development of a messenger RNA (mRNA) therapy that achieved sustained metabolic correction in a mouse model of propionic acidaemia.

The researchers’ goal was straightforward: to produce functional PCC enzyme in vivo, thereby restoring liver metabolic function in patients with either PCCA or PCCB deficiency. To achieve this aim, the researchers devised lipid nanoparticles loaded with mRNAs encoding both human PCCA and PCCB. In cultured human fibroblasts treated with dual mRNA-loaded lipid nanoparticles, PCC expression was localized to mitochondria, and further optimization of the PCCA to PCCB mRNA molar ratio revealed that a 1:1 ratio yielded the highest PCC enzymatic activity in these cells. After a single intravenous dose of dual mRNA-loaded lipid nanoparticles into a hypomorphic mouse model of propionic acidaemia, levels of PCCA and PCCB in the liver were similar to typical levels in human liver. Given the need for repeat dosing to maintain PCC expression, the researchers conducted two long-term studies in propionic acidaemia hypomorphic mice: 0.5 or 2 mg/kg intravenous mRNA dosing every 3 weeks over 3 months, or 0.5 or 1 mg/kg monthly intravenous mRNA dosing over 6 months. Both studies showed dose-dependent increases in hepatic PCC activity and reductions in primary biomarkers in plasma (such as 2-methylcitrate, 3-hydroxypropionate and propionylcarnitine to acetylcarnitine ratio), with no observed adverse effects, indicating favourable tolerability. However, the study has some limitations: it did not assess whether treated mice developed antibodies against human PCC, and many symptoms of propionic acidaemia in patients are not present in propionic acidaemia hypomorphic mice, both of which could potentially limit clinical translation of these findings.