Characterising a healthy adult with a rare HAO1 knockout to support a therapeutic strategy for primary hyperoxaluria

Tracy L McGregor, Karen A Hunt, Elaine Yee, Dan Mason, Paul Nioi, Simina Ticau, Marissa Pelosi, Perry R Loken, Sarah Finer, Deborah A Lawlor, Eric B Fauman, Qin Qin Huang, Christopher J Griffiths, Daniel G MacArthur, Richard C Trembath, Devin Oglesbee, John C Lieske, David V Erbe, John Wright, David A van Heel

    Research output: Contribution to journalArticle (Academic Journal)peer-review

    17 Citations (Scopus)


    By sequencing autozygous human populations, we identified a healthy adult woman with lifelong complete knockout of HAO1 (expected ~1 in 30 million outbred people). HAO1 (glycolate oxidase) silencing is the mechanism of lumasiran, an investigational RNA interference therapeutic for primary hyperoxaluria type 1. Her plasma glycolate levels were 12 times, and urinary glycolate 6 times, the upper limit of normal observed in healthy reference individuals (n = 67). Plasma metabolomics and lipidomics (1871 biochemicals) revealed 18 markedly elevated biochemicals (>5 sd outliers versus n = 25 controls) suggesting additional HAO1 effects. Comparison with lumasiran preclinical and clinical trial data suggested she has <2% residual glycolate oxidase activity. Cell line p.Leu333SerfsTer4 expression showed markedly reduced HAO1 protein levels and cellular protein mis-localisation. In this woman, lifelong HAO1 knockout is safe and without clinical phenotype, de-risking a therapeutic approach and informing therapeutic mechanisms. Unlocking evidence from the diversity of human genetic variation can facilitate drug development.

    Original languageEnglish
    Publication statusPublished - 24 Mar 2020

    Bibliographical note

    © 2020, McGregor et al.


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