In the last decades careful clinical and pharmacological management have significantly improved the clinical outcomes in patients with propionic acidemia.  However, the morbidity of the disease remains high and more effective therapies are highly needed.

We have generated a fish model of propionic acidemia using the Japanese medaka fish (Oryzias latipes; shown in the figure) as a tool for better understanding disease pathogenesis and for investigation of novel therapies. Fishes have been largely used to investigate developmental processes but more recently, they have also shown to be effective in modeling human metabolic diseases. Compared to other animal models used in biomedical research, such as rodents, fishes have several advantages including easy handling, availability in large number, and low cost. Moreover, fishes are well suited for high-throughput drug screening. These features make them excellent tools for investigation of novel therapies.

By genome editing technology, we introduced deleterious mutations in the fish gene that encodes for the enzyme deficient in propionic acidemia. Although they appeared healthy at hatching, these fishes showed progressive locomotor deficiency, lethargy and premature death in the days after hatching.  Importantly, affected fishes showed the biochemical hallmarks of propionic acidemia, including increased C3 levels and the presence of methylcitrate. Like in humans, the administration of a low-protein diet and carnitine reduced the severity of the disease in the fishes.

In conclusion, this novel animal model recapitulates several features observed in humans with propionic acidemia and it has potential to unravel the mechanisms underlying disease pathogenesis and to identify new therapies.

From the 2017 Summer OAA Newsletter