RNA interference (RNAi) is a natural biological pathway that inhibits gene 
expression by targeted degradation or translational inhibition of cytoplasmic 
mRNA by the RNA induced silencing complex. RNAi has long been exploited in 
laboratory research to study the biological consequences of the reduced 
expression of a gene of interest. More recently RNAi has been demonstrated as a 
therapeutic avenue for rare metabolic diseases. This review presents an overview 
of the cellular RNAi machinery as well as therapeutic RNAi design and delivery. 
As a clinical example we present primary hyperoxaluria, an ultrarare inherited 
disease of increased hepatic oxalate production which leads to recurrent calcium 
oxalate kidney stones. In the most common form of the disease (Type 1), 
end-stage kidney disease occurs in childhood or young adulthood, often 
necessitating combined kidney and liver transplantation. In this context we 
discuss nedosiran (Dicerna Pharmaceuticals, Inc.) and lumasiran (Alnylam 
Pharmaceuticals), which are both novel RNAi therapies for primary hyperoxaluria 
that selectively reduce hepatic expression of lactate dehydrogenase and 
glycolate oxidase respectively, reducing hepatic oxalate production and urinary 
oxalate levels. Finally, we consider future optimizations advances in RNAi 
therapies.