@article{6021ce9e982148428010200ebc7c17fb,
title = "Characterising a healthy adult with a rare hao1 knockout to support a therapeutic strategy for primary hyperoxaluria",
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.",
author = "McGregor, {Tracy L.} and Hunt, {Karen A.} and Elaine Yee and Dan Mason and Paul Nioi and Simina Ticau and Marissa Pelosi and Loken, {Perry R.} and Sarah Finer and Lawlor, {Deborah A.} and Fauman, {Eric B.} and Huang, {Qin Qin} and Griffiths, {Christopher J.} and Macarthur, {Daniel G.} and Trembath, {Richard C.} and Devin Oglesbee and Lieske, {John C.} and Erbe, {David V.} and John Wright and {van Heel}, {David A.}",
note = "Funding Information: Genes and Health is funded by Wellcome (WT102627, WT210561), the Medical Research Council (UK) (M009017), Higher Education Funding Council for England Catalyst, Barts Charity (845/1796), Health Data Research UK (for London substantive site), and research delivery support from the NHS National Institute for Health Research Clinical Research Network (North Thames). Born In Bradford is funded by Wellcome (WT101597MA), a joint grant from the UK Medical Research Council (MRC) and UK Economic and Social Science Research Council (ESRC) (MR/ N024397/1), the British Heart Foundation (CS/16/4/32482) and the National Institute for Health Research (NIHR) under its Collaboration for Applied Health Research and Care (CLAHRC) for York-shire and Humber. DAL is supported by, the British Heart Foundation (AA/18/7/34219), US National Institute of Health (R01 DK10324) and the European Research Council (669545); she works in a Unit that is supported by the University of Bristol and the MRC (MC_UU_00011/6), which supported DNA extraction from participants in BiB. Genes and Health received an unrestricted grant from Alnylam Pharmaceuticals for work performed in this manuscript. Born In Bradford received funding from Alnylam Pharmaceuticals for data extraction from clinical records. Alnylam Pharmaceuticals directly funded biochemical assays performed at the Mayo Clinic. We thank Eric Minikel for comments on gene constraint analyses. We thank Dr John Knight and Dr Hoy Shen for comments on the metabolomics data. We thank all of the volunteers participating in Genes and Health and Born in Bradford, and the staff who have recruited and collected data from volunteers. The views expressed in this paper are those of the authors and not necessarily any funders or others acknowledged here. Funder Grant reference number Author Wellcome WT102627 David A van Heel Wellcome WT210561 David A van Heel Medical Research Council M009017 David A van Heel. Funding Information: Genes and Health is funded by Wellcome (WT102627, WT210561), the Medical Research Council (UK) (M009017), Higher Education Funding Council for England Catalyst, Barts Charity (845/1796), Health Data Research UK (for London substantive site), and research delivery support from the NHS National Institute for Health Research Clinical Research Network (North Thames). Funding Information: Born In Bradford is funded by Wellcome (WT101597MA), a joint grant from the UK Medical Research Council (MRC) and UK Economic and Social Science Research Council (ESRC) (MR/ N024397/1), the British Heart Foundation (CS/16/4/32482) and the National Institute for Health Research (NIHR) under its Collaboration for Applied Health Research and Care (CLAHRC) for Yorkshire and Humber. DAL is supported by, the British Heart Foundation (AA/18/7/34219), US National Institute of Health (R01 DK10324) and the European Research Council (669545); she works in a Unit that is supported by the University of Bristol and the MRC (MC_UU_00011/6), which supported DNA extraction from participants in BiB. Funding Information: Tracy L McGregor, Elaine Yee, Paul Nioi, Simina Ticau, Marissa Pelosi, David V Erbe: employee of Alnylam Pharmaceuticals. Eric B Fauman: 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. The other authors declare that no competing interests exist. Funding Information: Genes and Health received an unrestricted grant from Alnylam Pharmaceuticals for work performed in this manuscript. Born In Bradford received funding from Alnylam Pharmaceuticals for data extraction from clinical records. Alnylam Pharmaceuticals directly funded biochemical assays performed at the Mayo Clinic. Publisher Copyright: {\textcopyright} McGregor et al.",
year = "2020",
month = mar,
doi = "10.7554/eLife.54363",
language = "English (US)",
volume = "9",
journal = "eLife",
issn = "2050-084X",
publisher = "eLife Sciences Publications",
}