Researchers at Oregon Health & Science University in Portland created a new mouse model of long-chain 3-hydroxy-acyl-CoA dehydrogenase (LCHAD) deficiency, a type of long-chain fatty acid oxidation disorder (LCFAOD).

The model, which is viable and recapitulates some clinical features of the disease, was presented by Garen Gaston, PhD, at the 2022 lecture series of the International Network for Fatty Acid Oxidation Research and Management (INFORM).

Researchers have previously developed other mouse models of LCHAD deficiency. However, these models were neonatal lethal, which limited their usefulness.


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Here, the team led by Melanie B. Gillingham, PhD, RD, LD, made use of the CRISPR/Cas-9 system to knock in the G1528C mutation in the HADHA gene, which is the most common mutation seen in people with LCHAD deficiency.

Read more about the types of LCFAOD.

The researchers then characterized the mouse model and reported that even though the mice had reduced viability in breeding, they had growth rates comparable to wild-type animals. They also showed classic signs of fatty acid oxidation disorders showing fasting, exercise, and cardiac differences. 

“The G1528C mouse model also shows LCHADD specific symptoms such as high 3-hydroxyacyl carnitines, possible neuropathy, and retinopathy,” Dr. Gaston said, adding that this retinopathy may be exacerbated by a high-fat diet. Finally, the animals displayed abnormalities in the morphology of their mitochondria, which can be indicative of mitochondrial stress and interruptions in the mitochondrial fusion machinery. 

The next steps will include further characterizing the retinopathy seen in these animals and assessing the potential benefits of gene therapy, using the model. 

The HADHA gene encodes one of the enzymes in the trifunctional protein complex, which is made of 3 different enzymes that each play a different role in long-chain fatty acid metabolism inside the mitochondria. Mutation in the HADHA gene disrupts the function of the whole complex, leading to the accumulation of long-chain fatty acids causing damage and resulting in energy deficiency.

Reference

Gaston G. A novel G1528C knock-in model of LCHAD deficiency recapitulates aspects of the human clinical phenotype. Lecture presented as part of International Network for Fatty Acid Oxidation Research and Management (INFORM) 2022 lecture series: March 28, 2022; Virtual.