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Lumasiran Mechanism PH1 Substrate Reduction — ESENeph MCQ

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HardRenal Stone DiseaseLumasiran Mechanism PH1 Substrate ReductionESENeph

A 45-year-old man with primary hyperoxaluria type 1 is on Lumasiran. His urinary oxalate has decreased by 65%. His eGFR is 45 mL/min/1.73m2 and stable. He asks how Lumasiran works. What is the mechanism?

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Correct answer: D — Lumasiran is an RNA interference (siRNA) therapy that silences the gene encoding glycolate oxidase (HAO1) in hepatocytes – this reduces the substrate available for oxalate production, lowering urinary and plasma oxalate

In PH1, the defective AGXT enzyme normally converts glyoxylate to glycine. Without AGXT, glyoxylate is instead oxidised to oxalate (by lactate dehydrogenase) and reduced to glycolate (by glyoxylate reductase). Glycolate is then reoxidised to glyoxylate by glycolate oxidase (HAO1), amplifying the cycle. Lumasiran silences HAO1, breaking this amplification loop and reducing glyoxylate (and therefore oxalate) production by ~50-65%. This is a substrate reduction strategy rather than enzyme replacement. The ILLUMINATE trials showed dramatic urinary oxalate reduction. It is given SC monthly for 3 doses then quarterly.

Reference: NICE HST10 2021 – Lumasiran; ILLUMINATE-A Trial – NEJM 2021