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

eLife

Elaine Yee¹  Tracy L McGregor¹  David V Erbe¹  Paul Nioi¹  Simina Ticau¹  Marissa Pelosi¹  Daniel G MacArthur²  Karen A Hunt³  David A van Heel³  Sarah Finer³  Christopher J Griffiths³  John Wright⁴  Dan Mason⁴  Eric B Fauman⁵  Deborah A Lawlor⁶  John C Lieske⁷  Devin Oglesbee⁷  Perry R Loken⁷  Richard C Trembath⁸  Qin Qin Huang⁹ 

[1] Alnylam Pharmaceuticals, Cambridge, United States;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;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;Population Health Science, Bristol Medical School, Bristol University, Bristol, United Kingdom;Bristol NIHR Biomedical Research Centre, 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;    Human;   

DOI  :  10.7554/eLife.54363

来源: publisher

【 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】

CC BY