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Elife. 2020 Mar 24;9. pii: e54363. doi: 10.7554/eLife.54363.

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

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Alnylam Pharmaceuticals, Cambridge, United States.
Blizard Institute and Institute for Population Health Sciences, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom.
Bradford Institute for Health Research, Bradford Teaching Hospitals National Health Service (NHS) Foundation Trust, Bradford, United Kingdom.
Mayo Clinic, Division of Nephrology and Hypertension, Rochester, United States.
MRC Integrative Epidemiology Unit at the University of Bristol, Oakfield House, Oakfield Grove, Bristol, United Kingdom.
Population Health Science, Bristol Medical School, Bristol University, Bristol, United Kingdom.
Bristol NIHR Biomedical Research Centre, Bristol, United Kingdom.
Internal Medicine Research Unit, Pfizer Worldwide Research, Development and Medical, Cambridge, United States.
Wellcome Sanger Institute, Hinxton, United Kingdom.
Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, United States.
Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, United States.
School of Basic and Medical Biosciences, Faculty of Life Sciences and Medicine, King's College London, London, United Kingdom.


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.


RNAi theraputic; genetics; genomics; glycolate; human; hyperoxaluria; knockouts

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Conflict of interest statement

TM, EY, PN, ST, MP, DE employee of Alnylam Pharmaceuticals, KH, DM, PL, SF, DL, QH, CG, DM, RT, DO, JL, JW, Dv No competing interests declared, EF is affiliated with Pfizer Worldwide Research. The author has no financial interests to declare. Contributed as an individual and the work was not part of a Pfizer collaboration nor was it funded by Pfizer.

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