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

Publication Details

eLife

March 2020

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Author(s)

Tracy L McGregor¹, Karen A Hunt², Elaine Yee¹, Dan Mason³, Paul Nioi¹, Simina Ticau¹, Marissa Pelosi¹, Perry R Loken⁴, Sarah Finer², Deborah A Lawlor ^{5 6 7}, Eric B Fauman⁸, Qin Qin Huang⁹, Christopher J Griffiths², Daniel G MacArthur ^{10 11}, Richard C Trembath¹², Devin Oglesbee⁴, John C Lieske⁴, David V Erbe¹, John Wright³, David A van Heel²

Affiliations

¹Alnylam Pharmaceuticals, Cambridge, United States; ²Blizard Institute and Institute for Population Health Sciences, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom; ³Bradford Institute for Health Research, Bradford Teaching Hospitals National Health Service (NHS) Foundation Trust, Bradford, United Kingdom; ⁴Mayo Clinic, Division of Nephrology and Hypertension, Rochester, United States; ⁵MRC Integrative Epidemiology Unit at the University of Bristol, Oakfield House, Oakfield Grove, Bristol, United Kingdom; ⁶Population Health Science, Bristol Medical School, Bristol University, Bristol, United Kingdom; ⁷Bristol NIHR Biomedical Research Centre, Bristol, United Kingdom; ⁸Internal Medicine Research Unit, Pfizer Worldwide Research, Development and Medical, Cambridge, United States; ⁹Wellcome Sanger Institute, Hinxton, United Kingdom; ¹⁰Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, United States; ¹¹Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, United States; ¹²School of Basic and Medical Biosciences, Faculty of Life Sciences and Medicine, King's College London, London, United Kingdom

Abstract

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.