Characterising a healthy adult with a rare HAO1 knockout to support a therapeutic strategy for primary hyperoxaluria
- Alnylam Pharmaceuticals, United States
- Queen Mary University of London, United Kingdom
- Bradford Teaching Hospitals NHS Foundation Trust, United Kingdom
- Mayo Clinic, United States
- University of Bristol, United Kingdom
- Pfizer Worldwide Research, United States
- Wellcome Sanger Institute, United Kingdom
- Broad Institute of MIT and Harvard, United States
- Kings College 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 (>5sd 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.
Data availability
All metabolomic data is available in full in the Supplementary Files.
Article and author information
Author details
Funding
Wellcome (WT102627)
- David A van Heel
Wellcome (WT210561)
- David A van Heel
Medical Research Council (M009017)
- David A van Heel
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Human subjects: The HAO1 knockout volunteer took part in both the Born In Bradford study and the Genes & Health study. Volunteers providing control samples took part in the Genes & Health study. Ethical approval was obtained from Bradford National Research Ethics Committee (06/Q1202/48) and the South East London National Research Ethics Committee (14/LO/1240). Informed consent and consent to publish was obtained.
Copyright
© 2020, McGregor et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Characterising a healthy adult with a rare HAO1 knockout to support a therapeutic strategy for primary hyperoxaluria
eLife 9:e54363.
https://doi.org/10.7554/eLife.54363
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