1. Genetics and Genomics

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

  1. Tracy L McGregor
  2. Karen A Hunt
  3. Elaine Yee
  4. Dan Mason
  5. Paul Nioi
  6. Simina Ticau
  7. Marissa Pelosi
  8. Perry R Loken
  9. Sarah Finer
  10. Deborah A Lawlor
  11. Eric B Fauman
  12. Qin Qin Huang
  13. Christopher J Griffiths
  14. Daniel G MacArthur
  15. Richard C Trembath
  16. Devin Oglesbee
  17. John C Lieske
  18. David V Erbe
  19. John Wright
  20. David A van Heel  Is a corresponding author
  1. Alnylam Pharmaceuticals, United States
  2. Queen Mary University of London, United Kingdom
  3. Bradford Teaching Hospitals NHS Foundation Trust, United Kingdom
  4. Mayo Clinic, United States
  5. University of Bristol, United Kingdom
  6. Pfizer Worldwide Research, United States
  7. Wellcome Sanger Institute, United Kingdom
  8. Broad Institute of MIT and Harvard, United States
  9. Kings College London, United Kingdom
https://doi.org/10.7554/eLife.54363
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Cite this article
  1. Tracy L McGregor
  2. Karen A Hunt
  3. Elaine Yee
  4. Dan Mason
  5. Paul Nioi
  6. Simina Ticau
  7. Marissa Pelosi
  8. Perry R Loken
  9. Sarah Finer
  10. Deborah A Lawlor
  11. Eric B Fauman
  12. Qin Qin Huang
  13. Christopher J Griffiths
  14. Daniel G MacArthur
  15. Richard C Trembath
  16. Devin Oglesbee
  17. John C Lieske
  18. David V Erbe
  19. John Wright
  20. David A van Heel
(2020)
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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  3. Download .RIS

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

  1. Tracy L McGregor

    Clinical Research, Alnylam Pharmaceuticals, Cambridge, United States
    Competing interests
    Tracy L McGregor, employee of Alnylam Pharmaceuticals.

  2. Karen A Hunt

    Blizard Institute, Queen Mary University of London, London, United Kingdom
    Competing interests
    No competing interests declared.

  3. Elaine Yee

    Clinical Research, Alnylam Pharmaceuticals, Cambridge, United States
    Competing interests
    Elaine Yee, employee of Alnylam Pharmaceuticals.

  4. Dan Mason

    Bradford Institute for Health Research, Bradford Teaching Hospitals NHS Foundation Trust, Bradford, United Kingdom
    Competing interests
    No competing interests declared.

  5. Paul Nioi

    Clinical Research, Alnylam Pharmaceuticals, Cambridge, United States
    Competing interests
    Paul Nioi, employee of Alnylam Pharmaceuticals.

  6. Simina Ticau

    Clinical Research, Alnylam Pharmaceuticals, Cambridge, United States
    Competing interests
    Simina Ticau, employee of Alnylam Pharmaceuticals.

  7. Marissa Pelosi

    Clinical Research, Alnylam Pharmaceuticals, Cambridge, United States
    Competing interests
    Marissa Pelosi, employee of Alnylam Pharmaceuticals.

  8. Perry R Loken

    Division of Nephrology and Hypertension, Mayo Clinic, Rochester, United States
    Competing interests
    No competing interests declared.

  9. Sarah Finer

    Institute of Population and Health Science, Queen Mary University of London, London, United Kingdom
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2684-4653

  10. Deborah A Lawlor

    University of Bristol, Bristol, United Kingdom
    Competing interests
    No competing interests declared.

  11. Eric B Fauman

    Internal Medicine Research Unit, Pfizer Worldwide Research, Cambridge, United States
    Competing interests
    Eric B Fauman, Eric B. Fauman is affiliated with Pfizer Worldwide Research. The author has no financial interests to declare. Eric B. Fauman contributed as an individual and the work was not part of a Pfizer collaboration nor was it funded by Pfizer..

  12. Qin Qin Huang

    Medical and Population Genomics, Wellcome Sanger Institute, Hinxton, United Kingdom
    Competing interests
    No competing interests declared.

  13. Christopher J Griffiths

    Institute of Population and Health Science, Queen Mary University of London, London, United Kingdom
    Competing interests
    No competing interests declared.

  14. Daniel G MacArthur

    Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, United States
    Competing interests
    No competing interests declared.

  15. Richard C Trembath

    Faculty of Life Sciences and Medicine, Kings College London, London, United Kingdom
    Competing interests
    No competing interests declared.

  16. Devin Oglesbee

    Division of Nephrology and Hypertension, Mayo Clinic, Rochester, United States
    Competing interests
    No competing interests declared.

  17. John C Lieske

    Nehrology and Hypertension, Mayo Clinic, Rochester, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0202-5944

  18. David V Erbe

    Clinical Research, Alnylam Pharmaceuticals, Cambridge, United States
    Competing interests
    David V Erbe, employee of Alnylam Pharmaceuticals.

  19. John Wright

    Bradford Institute for Health Research, Bradford Teaching Hospitals NHS Foundation Trust, Bradford, United Kingdom
    Competing interests
    No competing interests declared.

  20. David A van Heel

    Blizard Institute, Queen Mary University of London, London, United Kingdom
    For correspondence
    d.vanheel@qmul.ac.uk
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0637-2265

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.

Reviewing Editor

  1. Alison Goate, Icahn School of Medicine at Mount Sinai, United States

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.

Version history

  1. Received: December 11, 2019
  2. Accepted: March 23, 2020
  3. Accepted Manuscript published: March 24, 2020 (version 1)
  4. Version of Record published: March 31, 2020 (version 2)

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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  1. Tracy L McGregor
  2. Karen A Hunt
  3. Elaine Yee
  4. Dan Mason
  5. Paul Nioi
  6. Simina Ticau
  7. Marissa Pelosi
  8. Perry R Loken
  9. Sarah Finer
  10. Deborah A Lawlor
  11. Eric B Fauman
  12. Qin Qin Huang
  13. Christopher J Griffiths
  14. Daniel G MacArthur
  15. Richard C Trembath
  16. Devin Oglesbee
  17. John C Lieske
  18. David V Erbe
  19. John Wright
  20. David A van Heel
(2020)
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

Share this article

https://doi.org/10.7554/eLife.54363

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