LDHA (lactate dehydrogenase A) mRNA

Class

GalNAc-conjugated RNAi therapeutic (siRNA)

Pathway

Hepatic glyoxylate/oxalate synthesis pathway (primary hyperoxaluria)

Lactate dehydrogenase A (LDHA) is an enzyme best known for interconverting pyruvate and lactate in cellular energy metabolism, but in the liver it also carries out the final step that converts glyoxylate into oxalate. In primary hyperoxaluria, inherited defects in earlier steps of glyoxylate handling cause this precursor to accumulate and be shunted toward oxalate production, and the resulting oxalate excess deposits as crystals in the kidneys, damaging renal tissue over time. Because LDHA acts downstream of several different genetic defects that can cause hyperoxaluria, reducing its activity can lower oxalate output regardless of which upstream enzyme is deficient, offering a shared therapeutic strategy across genetic subtypes. This mechanism is pursued using small interfering RNA (siRNA) technology conjugated to N-acetylgalactosamine (GalNAc), a sugar moiety that directs the molecule specifically to liver cells, where it degrades LDHA messenger RNA and reduces production of the enzyme itself. This approach broadly matters wherever excess hepatic oxalate synthesis drives disease, and it illustrates a wider RNAi strategy of silencing a shared downstream node rather than each of several possible upstream causes.