A German study published in September 2022 in Molecular Therapy supports a clinical trial of “periodic low-dose intramuscular administration” of an mRNA-based therapy against Hereditary tyrosinemia 1. This is a recessive genetic disease of amino acid metabolism, characterised by deficiency of fumarylacetoacetate hydrolase (FAH). HT1 is estimated to affect 1 in 100,000 despite regional differences. It is particularly harmful for untreated children, who “usually do not survive past the age of 10 years”.  

At present there are only limited treatment options, with patients following a “strict diet” and facing “complications” such as liver cancer and progressive neurocognitive decline. Thus, the need for therapies to “standardise metabolite levels and promise normal development” is pressing.  

Current options 

The current standard of care for HT1 involves an oral drug and a life-long diet low in phenylalanine and tyrosine. However, the study suggests that some adults do not respond to treatment, and some children following the programme experience developmental difficulties. The novel approach focuses on mRNA-based therapy, described as a “powerful tool with tremendous potential to treat a variety of indications”.  

The mouse model 

The study describes how “repeated intravenous or intramuscular administration of lipid nanoparticle-formulated human FAH mRNA” prompted FAH protein synthesis in deficient mouse livers. Furthermore, it “stabilised body weight, normalised pathologic increases in metabolites after nitisinone withdrawal” as well as reducing the likelihood of early death.  

The authors concluded that “very low amounts” of FAH expression in the liver were enough to remedy body weight loss. Additionally, repeated intravenous injections of FAH mRNA-LNPs provided a “valuable therapeutic approach” and repeated intramuscular injections led to the transport of these FAH mRNA-loaded LNPs to the liver via the blood stream.  

“These findings provide the potential basis for clinical application of mRNA technology to HT1 treatment”. 

To hear more about the potential presented by mRNA come to the World Vaccine Congress in Europe 2022.