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
Affiliations
Tracy L McGregor
Alnylam Pharmaceuticals, Cambridge, United States
Karen A Hunt
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
Elaine Yee
Alnylam Pharmaceuticals, Cambridge, United States
Dan Mason
Bradford Institute for Health Research, Bradford Teaching Hospitals National Health Service (NHS) Foundation Trust, Bradford, United Kingdom
Paul Nioi
Alnylam Pharmaceuticals, Cambridge, United States
Simina Ticau
Alnylam Pharmaceuticals, Cambridge, United States
Marissa Pelosi
Alnylam Pharmaceuticals, Cambridge, United States
Perry R Loken
Mayo Clinic, Division of Nephrology and Hypertension, Rochester, 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
Deborah A Lawlor
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
Eric B Fauman
Internal Medicine Research Unit, Pfizer Worldwide Research, Development and Medical, Cambridge, United States
Qin Qin Huang
Wellcome Sanger Institute, Hinxton, United Kingdom
Christopher J Griffiths
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
Daniel G MacArthur
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
Richard C Trembath
School of Basic and Medical Biosciences, Faculty of Life Sciences and Medicine, King’s College London, London, United Kingdom
Devin Oglesbee
Mayo Clinic, Division of Nephrology and Hypertension, Rochester, 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
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.
