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

eLife

Qin Qin Huang¹  Eric B Fauman²  John C Lieske³  Elaine Yee⁴  Simina Ticau⁴  Marissa Pelosi⁴  Paul Nioi⁴  Tracy L McGregor⁴  Devin Oglesbee⁵  Karen A Hunt⁶  Sarah Finer⁶  Richard C Trembath⁶  Dan Mason⁷  Christopher J Griffiths⁸  Deborah A Lawlor⁹  David A van Heel^1,10  Perry R Loken^1,10  John Wright^1,10  David V Erbe^1,11  Daniel G MacArthur^1,12 

[1] Bristol NIHR Biomedical Research Centre, Bristol, United Kingdom;Population Health Science, Bristol Medical School, Bristol University, Bristol, United Kingdom;Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, United States;Alnylam Pharmaceuticals, Cambridge, United States;Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, 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;Internal Medicine Research Unit, Pfizer Worldwide Research, Development and Medical, Cambridge, United States;MRC Integrative Epidemiology Unit at the University of Bristol, Oakfield House, Oakfield Grove, Bristol, United Kingdom;Mayo Clinic, Division of Nephrology and Hypertension, Rochester, United States;School of Basic and Medical Biosciences, Faculty of Life Sciences and Medicine, King’s College London, London, United Kingdom;Wellcome Sanger Institute, Hinxton, United Kingdom;

关键词: knockouts;    hyperoxaluria;    RNAi theraputic;    glycolate;   

DOI  :  10.7554/eLife.54363

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown